Pharmaceutical compositions providing enhanced drug concentrations

ABSTRACT

A drug in a solubility-improved form is combined with a concentration-enhancing polymer in a sufficient amount so that the combination provides substantially enhanced drug concentration in a use environment relative to a control comprising the same amount of the same solubility-improved form of drug without the concentration-enhancing polymer.

BACKGROUND OF THE INVENTION

The invention relates to compositions comprising a combination of a drugand a concentration-enhancing polymer that enhances the concentration ofthe drug in a use environment relative to control compositions that arefree from the concentration-enhancing polymer.

Low-solubility drugs often show poor bioavailability or irregularabsorption, the degree of irregularity being affected by factors such asdose level, fed state of the patient, and form of the drug. Increasingthe bioavailability of low-solubility drugs has been the subject of muchresearch. Increasing bioavailability hinges on improving theconcentration of the drug in solution to improve absorption.

It is known that many low-solubility drugs can be formulated so as toincrease the maximum concentration of the drug that will dissolve in anaqueous solution in in vitro tests. When such a drug in asolubility-improved form is initially dissolved in an environment ofuse, such as in gastric fluid, the solubility-improved form of the druginitially provides a higher concentration of dissolved drug in theenvironment of use relative to other forms of the drug and relative tothe equilibrium concentration of the drug. In addition, it has beenshown that when such forms are tested in vivo they can enhance therelative bioavailability of the drug, presumably by enhancing, at leasttemporarily, the concentration of dissolved drug present in thegastrointestinal (GI) tract. However, as discussed below, the higherconcentration obtained is often only temporary, with thesolubility-improved drug form quickly converting to the low-solubilityform after delivery to a use environment.

For example, it is known that some low-solubility drugs may beformulated in highly soluble salt forms that provide temporaryimprovements in the concentration of the drug in a use environmentrelative to another salt form of the drug. An example of such a drug issertraline, which in the lactate salt form has a higher aqueoussolubility at pH 3 than the HCl salt form. However, when ahigh-solubility salt form such as sertraline lactate is dosed to anaqueous solution (either in vitro or in vivo) that has both high levelsof chloride present as well as buffers to control the pH, the enhancedsolubility of the sertraline lactate is either short lived or notachieved at all since the sertraline can quickly convert to crystallineor amorphous HCl or free base forms that have lower solubility thansertraline lactate.

Another drug form known to provide, at least temporarily, increasedconcentrations in solution of low-solubility drugs consists of drug in ahydrate or solvate crystalline form of the drug. Such forms often havehigher aqueous solubility relative to the lowest solubility crystallineform and, therefore, provide higher concentrations of drug.

It is known that some drugs are capable of forming more than one crystalstructure, despite having identical chemical compositions. (This is incontrast to salt forms, solvates, or hydrates that have varying chemicalcompositions.) These various crystal structures are often referred to aspolymorphs. Polymorphs comprise another drug form that temporarilyprovides increased concentrations in solution. Some polymorphs, alsoreferred to herein as “high-energy crystalline forms,” have higheraqueous solubility and therefore can provide enhanced aqueousconcentration of the drug relative to other crystal structures andrelative to the equilibrium concentration.

It is also well known that the amorphous form of a low-solubility drugthat is capable of existing in either the crystalline or amorphous formmay also temporarily provide a greater aqueous concentration of drugrelative to the equilibrium concentration of drug in a use environment.It is believed that the amorphous form of the drug dissolves morerapidly than the crystalline form, often dissolving faster than the drugcan precipitate from solution. As a result, the amorphous form maytemporarily provide a greater-than equilibrium concentration of drug.

Another method that can temporarily provide a greater than equilibriumdrug concentration is to include a solubilizing agent in the drug form.Such solubilizing agents promote the aqueous solubility of the drug. Anexample of the use of a solubilizing agent with a drug to increaseaqueous solubility is the use of solubilizing agents with sertraline. Asdisclosed in commonly assigned PCT Application No. 99/01120, now U.S.Pat. No. ______, when sertraline is codissolved in aqueous solution witha solubilizing agent, for example, citric acid, the solubility ofsertraline is dramatically increased. As mentioned above, whensertraline HCl is dosed along with citric acid to a chloride-containingbuffer solution or the GI tract, the maximum sertraline concentrationachieved can exceed the solubility of sertraline HCl. This concentrationenhancement is thought to be partly due to a locally lower pH in the useenvironment due to the presence of the citric acid and partly due to thepresence of citrate counter ions, as sertraline citrate is more solublethan sertraline chloride. However, the enhanced concentration istypically short-lived as sertraline quickly converts to a low-solubilityform which could be, depending on the use environment, the solidcrystalline or amorphous HCl salt and/or crystalline or amorphous freebase.

Yet another technique for temporarily achieving a greater thanequilibrium concentration of drug in a use environment is to formulatethe drug as an aqueous or organic solution. For example, drug can bedissolved in polyethylene glycol (PEG) or an aqueous solution of PEG towhich an acid or base may be added or the drug may be dissolved in anaqueous solution of an acid or base. Alternatively, the drug can bedissolved in a pharmaceutically acceptable organic liquid such asglycerol, mono-, di-, or triglycerides, fats or oils.

While these solubility-improved drug forms show initially enhancedconcentration of the drug in a use environment, nevertheless theimproved concentration is often short-lived. Typically, the initiallyenhanced drug concentration is only temporary and quickly returns to thelower equilibrium concentration. For example, while a particular saltform of a basic drug may show improved initial aqueous concentration,the drug often rapidly converts in gastric fluid to another salt form(typically the HCl salt form) that has a much lower equilibriumconcentration. In other cases, the drug maintains acceptable solubilityin the low pH gastric solution, but precipitates typically as thefree-base form of the drug upon passing into the small intestine wherethe pH is high, typically from 4.4 to 7.5. Since drug absorption occursprimarily in the intestines, such drug dosage forms that do not sustainhigh concentration of the drug in an intestinal solution typically yieldonly minor improvements in bioavailability. Likewise, a high-solubilitysalt form of an acidic drug can rapidly convert to another salt formthat has a much lower equilibrium concentration. Similar effects areobserved even for high solubility salt forms of zwitterionic drugs.Similarly, once the high-energy crystalline form of a drug (e.g., apolymorph) dissolves, the drug often rapidly precipitates orcrystallizes from solution as it changes to a lower energy crystallineform or an amorphous form with lower solubility which causesconcentration of dissolved drug to approach a lower equilibriumconcentration.

One approach to increase the bioavailability of low-solubility drugs hasinvolved forming amorphous dispersions of drugs with polymers. Examplesof attempts to increase drug concentration by foaming a dispersion ofthe drug with a polymer include Lahr et al., U.S. Pat. No. 5,368,864,Kanikanti et al., U.S. Pat. No. 5,707,655, and Nakamichi et al., U.S.Pat. No. 5,456,923.

However, creating an amorphous dispersion of a drug and polymer(s) doeshave some drawbacks. There is a risk that in the process of creating thedispersion, the drug will be altered. For example, some drugs maydegrade at the elevated temperatures used to form some dispersions. Someprocesses use organic solvents which must be thoroughly removed to avoiddrug degradation. Solvents must be chosen which dissolve both the drugand the polymer. The process of forming such dispersions is alsotime-consuming and expensive. In addition, the dispersions may in somecases be unstable and may either chemically degrade over time atmoderate temperature and humidity levels or the drug may convert to alower energy and lower solubility amorphous or crystalline form.

Increasing drug solubilization by using combinations of drug and polymerhas also been described. For example, Martin et al., U.S. Pat. No.4,344,934 mixed poorly-soluble drugs with polymers such as hydroxypropylmethyl cellulose (HPMC) and added an aqueous surfactant solution to thedrug-polymer mixture. While this results in improved dissolution, thereis only slight enhancement of drug concentration relative to theequilibrium concentration. Piergiorgio et al., U.S. Pat. No. 4,880,623used solvent processing to co-precipitate nifedipine with PEG andadsorbed this onto polymers such as HPMC, or onto other excipients.While increased drug bioavailability was observed, no comparison wasmade between different drug forms. Uedo et al., U.S. Pat. No. 5,093,372mixed the sparingly-soluble drug exifone with polymers such as HPMC toincrease bioavailability. However, this did not result in any enhanceddrug concentration of the drug/polymer mixture relative to the bulkcrystalline form of the drug.

In addition, combining drugs with solubilizing polymers is notuniversally available to improve bioavailability for all low-solubilitydrugs. Drug solubilization is usually highly dependent upon the chemicalstructure and physical properties of the specific drug and therefore theparticular polymer, if any, that may prove to solubilize the drug variesfrom drug to drug. It is often difficult and time-consuming to selectpolymers which achieve improved solubilization, since the drug-polymerinteraction is poorly understood. Often, addition of polymers simplyspeeds dissolution of the drug, as opposed to providing enhancedconcentration.

Usui, et al., Inhibitory Effects of Water-soluble Polymers onPrecipitation of RS-8359, Int'l J. of Pharmaceutics 154 (1997) 59-66,discloses the use of three polymers, namely hydroxy propyl methylcellulose, hydroxy propyl cellulose, and polyvinylpyrrolidone to inhibitprecipitation of the low-solubility drug RS-8359. The drug and polymerwere dissolved in a mixture of 0.5 N HCl and methanol, and then added toa phosphate buffer solution. Usui et al. observed that the particularpolymers inhibited crystallization of the drug.

Accordingly, what is still needed is a composition comprising a drugthat provides enhanced concentration of the drug in aqueous solutionrelative to the equilibrium concentration of the drug, that maintainsthe concentration of the drug in such a solution over time or at leastreduces the rate at which the drug concentration decreases from theenhanced concentration to the equilibrium concentration, that may beprepared using processes that will not alter or degrade the drug, thatmay be prepared without relying on solvent processing, that is stableunder typical storage conditions, that may be easily and cheaplyprepared and that ultimately enhances the bioavailability of poorlysoluble drugs. These needs and others that will become apparent to oneof ordinary skill are met by the present invention, which is summarizedand described in detail below.

BRIEF SUMMARY OF THE INVENTION

The present invention overcomes the drawbacks of the prior art byproviding a composition comprising (1) a drug in a solubility-improvedform and (2) a concentration-enhancing polymer.

In a first aspect of the invention, the concentration-enhancing polymeris combined with the drug form in a sufficient amount so that thecomposition provides a maximum concentration of the drug in a useenvironment that is at least 1.25-fold that of an equilibriumconcentration of the drug in the use environment without the polymerpresent. The composition also provides a concentration of the drug inthe use environment that exceeds the equilibrium concentration for alonger time than does a control composition that comprises an equivalentquantity of the drug in the solubility-improved form which is free fromthe concentration-enhancing polymer.

In a second aspect of the invention, the concentration-enhancing polymeris present in a sufficient amount so that the composition provides adissolution area under the concentration-versus-time curve (AUC) for aperiod of at least 90 minutes during the 1200 minutes immediatelyfollowing introduction to the use environment that is at least 1.25-foldthat of the corresponding area under the curve provided by the samecontrol composition mentioned above.

In a third aspect of the invention, the concentration-enhancing polymeris present in a sufficient amount so that the composition provides arelative bioavailability that is at least 1.25.

In a fourth aspect of the invention, a method is provided forco-administering to a patient in need of a drug (1) the drug in asolubility-improved form and (2) a concentration-enhancing polymer. Theconcentration-enhancing polymer is co-administered in a sufficientamount so that there is provided in the use environment of the patient amaximum concentration of the drug that is at least 1.25-fold that of theequilibrium concentration of the drug in the use environment of thepatient without the polymer present. The method also provides aconcentration of the drug in the use environment of the patient thatexceeds the equilibrium concentration for a longer time than does thecontrol composition mentioned above.

In a fifth aspect of the invention, a method is provided forco-administering to a patient in need of a drug (1) the drug in asolubility-improved form and (2) a concentration-enhancing polymer. Theconcentration-enhancing polymer is co-administered in a sufficientamount so that there is provided in the use environment of the patient adissolution area under the concentration-versus-time curve for a periodof at least 90 minutes, during the 1200 minutes immediately followingintroduction to the use environment of the patient, that is at least1.25-fold the corresponding area under the curve provided by the samecontrol composition mentioned above.

In a sixth aspect of the invention, a method is provided forco-administering to a patient in need of a drug (1) the drug in asolubility-improved form, and (2) a concentration-enhancing polymer. Theconcentration-enhancing polymer is co-administered in a sufficientamount so that there is provided a relative bioavailability at least1.25-fold.

The term “solubility-improved form” as employed herein refers to a formof the drug which has increased solubility relative to the least solubleform of the drug known. Thus, the term implies that a less soluble formof the drug exists and is either known or has been determined, i.e.,known, for example, from the scientific or patent literature, ordetermined by or otherwise known to the investigator. A“solubility-improved form” may consist of a highly soluble form of thedrug alone, may be a composition comprising a highly soluble form of thedrug plus inert excipients, or may be a composition comprising the drugin a poorly or highly soluble form and one or more excipients which havethe effect of increasing the solubility of the drug, regardless of thelength of time for which the solubility is increased. Examples of“solubility-improved forms” include but are not limited to: (1) acrystalline highly soluble form of the drug such as a salt; (2) ahigh-energy crystalline form of the drug; (3) a hydrate or solvatecrystalline form of a drug; (4) an amorphous form of a drug (for a drugthat may exist as either amorphous or crystalline); (5) a mixture of thedrug (amorphous or crystalline) and a solubilizing agent; or (6) asolution of the drug dissolved in an aqueous or organic liquid.

Alternatively, the term “solubility-improved form” refers to a form ofthe drug alone or in a composition as is described above that, whendelivered to an in vivo environment of use (such as, for example, thegastrointestinal tract of a mammal) or a physiologically relevant invitro solution (such as phosphate buffered saline or a Model FastedDuodenal solution described below) provides, or is capable of providing,at least temporarily, a concentration of drug that is at least 1.25-foldthe equilibrium concentration of drug in the use environment. (As usedhere, the term “equilibrium concentration” is defined below.)

A solubility-improved form of a drug is one that meets at least one ofthe above definitions.

Since the crystalline free base and crystalline hydrochloride forms of abasic drug generally have relatively low solubility relative to otherdrug forms and because solubilized drug generally precipitates from theuse environment of the GI tract of an animal as one of these crystallineforms (or their amorphous counterparts), a preferred solubility-improvedform of a basic drug is a form of the drug that has an aqueoussolubility at least 2-fold the solubility of the more soluble of thecrystalline hydrochloride salt and the crystalline free base drug form.

In a preferred embodiment of the invention, the concentration-enhancingpolymer has a hydrophobic portion and a hydrophilic portion. In a mostpreferred embodiment, the concentration-enhancing polymer is anionizable polymer that is soluble in a use environment whensignificantly ionized at physiologically relevant pHs.

The solid compositions of the present invention are generallycombinations comprising the solubility-improved form andconcentration-enhancing polymer. “Combination” as used herein means thatthe solubility-improved form and concentration-enhancing polymer may bein physical contact with each other or in close proximity but withoutthe necessity of being physically mixed. For example, the solidcomposition may be in the form of a multi-layer tablet, as known in theart, wherein one or more layers comprises the solubility-improved formand one or more different layers comprises the concentration-enhancingpolymer. Yet another example may constitute a coated tablet whereineither the solubility-improved form of the drug or theconcentration-enhancing polymer or both may be present in the tabletcore and the coating may comprise the solubility-improved form or theconcentration-enhancing polymer or both. Alternatively, the combinationcan be in the form of a simple dry physical mixture wherein both thesolubility-improved form and concentration-enhancing polymer are mixedin particulate form and wherein the particles of each, regardless ofsize, retain the same individual physical properties that they exhibitin bulk. Any conventional method used to mix the polymer and drugtogether such as physical mixing and dry or wet granulation, which doesnot substantially convert the drug and polymer to a moleculardispersion, may be used.

Alternatively, the drug and concentration-enhancing polymer may beco-administered to a patient in need of the drug. The drug andconcentration-enhancing polymer may be administered in separate or thesame dosage forms, and may also be administered at essentially the sametime or at different times.

However, compositions comprising dispersions, particularly moleculardispersions wherein the dispersion is formed prior to delivery to theuse environment, of drug and polymer as disclosed in the art discussedabove, form no part of this invention and are excluded therefrom. Ingeneral, a molecular dispersion of drug and polymer is one in which thephysical properties of the mixture, such as melting point orglass-transition temperature, are transformed from those characteristicof the bulk (i.e. undispersed) polymer and drug. In the compositions ofthe present invention, as disclosed above, the drug and polymer eachretain their individual respective physical properties, such as meltingpoint and/or glass-transition temperature. Thus, solid compositions madeby dissolving a drug plus the concentration-enhancing polymer in asolvent followed by drying from the solvent, or by co-grinding, or byextruding with heating, or by precipitation by mixing a solution of thepolymer and a solution of the drug such that a dispersion of polymer anddrug precipitates, or by other methods such that a molecular dispersionof drug and concentration-enhancing polymer is formed do not form a partof this invention.

Also not a part of this invention is the special case where a basic drugwith high gastric (pH 1 to 2) solubility and low intestinal solubility(pH 6 to 8) is dosed as its lowest-solubility form with aconcentration-enhancing polymer. In such cases, a high drugconcentration is achieved as a result of the effect of the naturallyoccurring acidic environment of the stomach rather than as a result ofutilizing a solubility-improved form of the drug. Since the keyinventive component of this invention is combining a solubility-improveddrug form with a concentration-enhancing polymer, cases in which a highdrug solubility is achieved solely as a result of the naturalenvironment of the stomach does not constitute a part of this invention.

The various aspects of the present invention have one or more of thefollowing advantages.

The solubility-improved form of the drug when dissolved in the useenvironment provides an initial concentration of drug that exceeds theequilibrium concentration of drug, while the concentration-enhancingpolymer retards the rate at which the initially enhanced drugconcentration falls to the equilibrium concentration. The result is thatthe compositions of the present invention provide an improveddissolution area-under-the-curve (“AUC”) that is greater than thatprovided by the drug alone. While not required to be within the scope ofthe present invention, in some aspects, the solubility-improved formprovides a maximum drug concentration that exceeds the maximum drugconcentration achieved by the drug alone. Nevertheless, the advantagesof the invention may be obtained by merely retarding the rate at whichthe enhanced drug concentration falls to the equilibrium concentration,even without increasing the maximum drug concentration relative to thedrug alone.

In any event, improving the AUC means that the compositions of thepresent invention may also provide enhanced bioavailability of the drugby increasing the concentration of drug which remains dissolved in theuse environment, particularly in the GI tract. Improving theconcentration of the drug in solution allows higher blood levels to beachieved, in some cases enabling an effective level to be reached or inother cases, allowing effective blood levels to be reached at lower drugdosage levels, which in turn decreases the amount of drug that must bedosed, reduces the blood level variability, and also decreases the sizeof the dosage form depending on the amount of polymer needed.Accordingly, the compositions of the present invention enable theeffective use of drugs having low aqueous solubility which otherwise donot have a sufficiently high bioavailability, to be effective, and alsoenhance bioavailability to reduce the required dose.

Furthermore, because the compositions of the present invention providefor a higher concentration in the use environment, and because once ahigh drug concentration is achieved the concentration tends to remainhigh due to inhibition of precipitation or crystallization of the drug,they reduce the adverse effects of chemical species present in the useenvironment such as chloride or hydrogen ions or bile salts on theabsorption of drug. Thus, in cases where the use environment is the GItract, the compositions of the present invention will show lessvariability on the fed/fast state of the human or animal.

In addition, for those forms in which the drug is present in acrystalline state, the drug is less likely to have its physical orchemical state altered by, for example, various degradation reactions,and in turn, its pharmaceutical characteristics altered duringpreparation of the dosage form or during storage relative to, forexample, a solid amorphous dispersion of the drug which can undergodegradation or crystallization upon storage. In addition, because thecompositions containing crystalline drug are simple physical mixtures(as opposed to dispersions), the compositions do not suffer the storagestability problems of many dispersions. The compositions, being in thenature of solid mixtures, or simple solutions, are also easily preparedusing conventional mixing techniques.

The foregoing and other objectives, features, and advantages of theinvention will be more readily understood upon consideration of thefollowing detailed description of the invention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The present invention provides a composition comprising a drug in asolubility-improved form and a concentration-enhancing polymer. Thesolubility-improved form may be a crystalline highly soluble salt formof the drug, a high-energy crystalline form of the drug (e.g., ahigh-solubility polymorph), a hydrate or solvate crystalline form of thedrug, an amorphous form of the drug, a mixture of the drug with asolubilizing agent, or a solution of the drug in an aqueous or organicliquid. Suitable drug(s) and suitable concentration-enhancing polymer(s)are discussed in detail below.

Solid drug in the solubility-improved form and concentration-enhancingpolymer are termed “simple physical mixtures” when they are combinedusing conventional mixing techniques such as combining and physicallystirring dry components together or mixing by dry- or wet-granulating.Thus, a simple physical mixture of drug and polymer means that in themixture, the drug has properties, such as melting point in the case ofcrystalline drug, or glass-transition temperature in the case ofamorphous drug, that match those properties of the drug alone. Thiscontrasts with a drug/polymer molecular dispersion for which no drugmelting point is observed and a glass-transition temperature is observedthat differs from the polymer and drug alone and varies as a function ofthe drug/polymer mass ratio in the dispersion.

The drug in the solubility-improved form and the concentration-enhancingpolymer can also be combined via co-administration of the two componentsto a use environment. By co-administration is meant that thesolubility-improved drug form is administered separately from, butwithin the same general time frame, as the concentration-enhancingpolymer. For example, the solubility-improved drug form can beadministered in its own dosage form that is taken at approximately thesame time as the concentration-enhancing polymer, which is in a separatedosage form. The time difference between administration of the drug inthe solubility-improved form and the concentration-enhancing polymer issuch that they come into physical contact in the use environment. Whenthey are not co-administered at the same time it is generally preferableto administer the concentration-enhancing polymer prior toadministration of the drug in the solubility-improved form.

It is known that many drugs are capable of existing in several forms andmay be formulated in a solubility-improved form to provide an initiallyenhanced aqueous concentration of the drug relative to the equilibriumconcentration of the lowest-solubility form of the drug. However, in theabsence of the concentration-enhancing polymer, the initially enhanceddrug concentration can often quickly decrease to approximately theequilibrium concentration of the drug as the drug precipitates orcrystallizes from solution. This may occur through a variety ofmechanisms. For example, a highly soluble salt form may, due to thepresence of other ions in the use environment, convert to another saltform having a lower equilibrium concentration. Dissolved drug may alsochange its ionic state, for example, by protonation or de-protonation,resulting in precipitation or crystallization from solution as a lowersolubility form. Alternatively, a high-energy crystalline form upondissolution may rapidly convert to the low-energy crystalline form,which has a lower equilibrium concentration. Likewise, the drug may bemixed with a solubilizing agent. For example, particularly when the drugis a base, the drug may have higher aqueous solubility at low pH. Such adrug may be mixed with a solubilizer such as an inorganic or organicacid. The acid may serve as a solubilizing agent by lowering the pHwithin the dosage form as well as that of the use environment near thedosage form, thus increasing the local solubility of the drug. However,as the drug diffuses away from the dosage form, the pH of the useenvironment can increase due to the lower concentration of thesolubilizing acid, thus decreasing drug solubility and resulting inprecipitation of the drug. Thus, such solubility-improved drug forms, bythemselves, generally have limited success in producing the desiredincrease in bioavailability. In some cases, precipitation orcrystallization as a low-solubility form is so fast that the maximumsolubility of the solubility-improved form is not even reached.

The key to the present invention was the recognition by the inventorsthat the initially enhanced concentration of the drug in solutionprovided by a drug in a solubility-improved form could be maintained,and in some cases enhanced, by retarding precipitation, crystallization,or conversion of the drug to lower solubility forms through the use of aconcentration-enhancing polymer. Thus, without implying any particularmechanism of action, it is believed that the concentration-enhancingpolymers of this invention may be viewed as acting as crystallization orprecipitation inhibitors. Surprisingly, this may be accomplished bysimply combining the concentration-enhancing polymer with the drug whenthe drug is in a solid form, in contrast to forming a dispersion of thedrug and polymer. Alternatively, the polymer can be coated ontodrug-containing tablets or beads or even administered separately but tothe same use environment as the solubility-improved drug form and stillfunction to maintain for a substantial time period a greater thanequilibrium drug concentration and, in turn, a higher bioavailability.In addition, when the drug is in the form of a solution in a liquid, thepolymer may be co-dissolved with the drug in the liquid, be suspended inthe liquid, or even comprise a capsule wall or coating that contains theliquid.

Since a drug can often exist in any of many solid crystalline oramorphous foams and because interconversion between these forms is oftenunpredictable, it may require a very short to a very long time for thedissolved drug concentration to reach its equilibrium value in anaqueous solution. In any case, the presence of theconcentration-enhancing polymer increases the time required for the drugconcentration to fall to equilibrium. In fact, when compositions of theinvention are dosed to a use environment such as the GI tract wheredissolved drug is absorbed from the GI fluids, much or all of the drugmay be absorbed prior to the drug being substantially converted to itslowest solubility form. Typical enhancements of dissolved drugconcentration over equilibrium drug concentration are on the order of1.25-fold to 20-fold, and in some cases 20-fold to 100-fold. Forexample, where the control provides an equilibrium concentration of 1mg/mL and the composition provides a maximum drug concentration of 1.25mg/mL, the composition provides a 1.25-fold enhancement.

While not wishing to be bound by a particular theory, it is believedthat the concentration-enhancing polymer(s) of the present inventiongenerally do not have the capacity to greatly solubilize insoluble drugs(that is, to increase the equilibrium solubility of free drug). Instead,it is believed the concentration-enhancing polymers primarily act toslow the rate of precipitation or crystallization of the drug after thedrug is initially dissolved. The presence of the concentration-enhancingpolymer(s) thus allows the initially increased or enhanced concentrationprovided by the solubility-improved form of the drug to be at leastpartially maintained for at least a few minutes and, in some cases, formany hours. In addition, in cases where dissolution of thesolubility-improved form of the drug is slow and precipitation of thelow-solubility drug form, in the absence of the concentration-enhancingpolymer, is fast, the presence of the concentration-enhancing polymermay result in the maximum concentration of drug observed beingsubstantially higher than that observed in the absence of the polymer.

One possible mechanism for improving the drug concentration involves theassociation of the concentration-enhancing polymer and dissolved drug toform “polymer/drug assemblies.” Such assemblies may constitute variousforms, including polymeric micelles, high-energy polymer-drug aggregatesranging in size from a few nanometers to 1000 nanometers,polymer-stabilized drug colloids or polymer/drug complexes. Analternative view is that as dissolved drug begins to precipitate orcrystallize from solution (e.g., as nucleation begins) the polymeradsorbs to these drug aggregates or nuclei, preventing, or at leastretarding, the nucleation or crystal-growth process. In any case, thepresence of the polymer serves to enhance the amount of drug that isdissolved or at least available for absorption. Drug present in thevarious drug/polymer assemblies listed above is apparently quite labileand may contribute to the drug absorption process.

The concentration-enhancing polymers of the present invention provideenhanced concentration of the drug in a use environment exceeding theequilibrium concentration for a longer period of time than a controlcomposition comprising an equivalent quantity of drug in thesolubility-improved form when subjected to a dissolution test. That is,even though the control composition may provide an enhancedconcentration of drug in the use environment that exceeds theequilibrium concentration, the control does so for a shorter period oftime than the compositions of the present invention which contain aconcentration-enhancing polymer. Preferably, the compositions of thepresent invention provide enhanced drug concentration that exceed theequilibrium concentration provided by a control composition for a periodof at least 15 minutes, preferably a period of at least 60 minutes, andmore preferably a period of at least 90 minutes longer than does thedrug concentration provided by a control composition that does notcontain the concentration-enhancing polymer.

As used herein, the term “concentration of drug” in solution or in a useenvironment refers to drug that may be dissolved in the form of solvatedmonomeric molecules, so called “free drug,” or any other drug-containingsubmicron structure, assembly, aggregate, colloid, or micelle. As usedherein, a “use environment” can be either the in vivo environment of theGI tract, subcutaneous spaces, vaginal tract, arterial and venous bloodvessels, pulmonary tract or intramuscular tissue of an animal, such as amammal and particularly a human, or the in vitro environment of a testsolution, such as phosphate buffered saline (PBS) or a Model FastedDuodenal (MFD) solution. An appropriate PBS solution is an aqueoussolution comprising 20 mM sodium phosphate, 47 mM potassium phosphate,87 mM NaCl and 0.2 mM KCl, adjusted to pH 6.5. An appropriate MFDsolution is the same PBS solution wherein additionally is present 7.3 mMsodium taurocholic acid and 1.4 mM of1-palmitoyl-2-oleyl-sn-glycero-3-phosphocholine.

The inventors have found, in some cases, strong evidence for theexistence of drug in the form of polymer/drug aggregates whencompositions of the invention are dissolved in a use environment. Inparticular, it has been found that when drug, in a solubility-improvedform, is dissolved in a use environment at a level that exceeds itsequilibrium solubility value along with concentration-enhancing polymer,that there is a large increase in the light scattered by the solution.Dynamic light-scattering measurements show that when only polymer (suchas HMPCAS or CAP) is dissolved that there are a small number of polymeraggregates in the 10 nm to 20 nm average size range. As drug is added tosuch solutions, there is generally little change in the light-scatteringsignal until the total concentration of drug exceeds the equilibriumsolubility of the drug. At these higher drug levels, thelighter-scattering signal increases dramatically and dynamiclight-scattering analysis shows that the average size of particles insolution have a much larger size, typically 50 nm to 1,000 nm, and insome cases from as small as 10 and up to 2,000 nm.

NMR analysis of such solutions (formed by compositions of the invention)as well as chemical analysis of any undissolved precipitate, show thatthe particles giving rise to this light-scattering signal are composedof polymer and drug. Although the composition of these polymer/drugaggregates varies with the specific identity of the drug andconcentration-enhancing polymer as well as their amounts, thepolymer/drug aggregates generally contain from about 5 wt % to about 90wt % polymer, the remainder comprising non-crystalline drug. Inaddition, the polymer/drug aggregates may also contain substantialamounts of water. Once the proper conditions are present, polymer/drugaggregates generally form rapidly, within a few minutes and are quitestable, often changing in amount and size by only 20% to 50% or lessover a 1- to 20-hour period, a physiologically relevant time frame.

In addition, NMR analysis of such solutions formed by dissolution of thecompositions of this invention in a use environment have been shown tohave “free drug” concentrations that exceed the crystalline drugsolubility by 1.5 fold to 10 fold or more and that exceed even theamorphous drug solubility. Such “supersaturated” drug concentrations maybe maintained for one hour up to 20 hours or longer, more than asufficient time to result in an increase in drug absorption rates andthe total amount of drug absorbed from the GI tract.

A composition of the invention can be tested in vivo or, moreconveniently, in vitro to ascertain whether it is within the scope ofthe invention. A composition can be dissolution-tested by adding it to aPBS or an MFD solution and agitating to promote dissolution. Acomposition or a method for administration of drug that meets at leastone or more of the concentration criteria in either PBS or MFD or meetsone or more of the concentration or bioavailability criteria when dosedorally to the GI tract of an animal, including a mammal such as a human,is a composition or method of this invention.

In one aspect, the compositions of the present invention comprising adrug in a solubility-improved form combined with aconcentration-enhancing polymer provide a maximum concentration of thedrug in a use environment that is at least 1.25-fold the equilibriumconcentration of drug in the use environment provided by a controlcomposition without polymer present. In addition, the drug concentrationprovided by the composition exceeds the equilibrium concentration for alonger period of time than does the drug concentration provided by aconventional control composition. The conventional or controlcomposition is the drug in the solubility-improved form alone orcombined with a weight of inert diluent equivalent to the weight ofconcentration-enhancing polymer in the inventive composition.Preferably, the maximum concentration of drug achieved with thecomposition of the present invention is at least 2-fold and morepreferably at least 3-fold the equilibrium concentration provided by thecontrol.

In scientific terms, the equilibrium concentration of drug is obtainedwhen the concentration of drug in solution does not change with time. Atthis point, the drug has converted to its lowest energy form that isaccessible from its specific environment. This form is typically thelowest solubility crystalline form of the drug. In some cases, the rateof formation of the lowest energy, lowest solubility form of the drugfrom in vitro or in vivo solutions can be exceedingly slow, requiringdays or months. Since the residence time of an orally dosed drug in theGI tract is typically only on the order of 24 hours, for purposes of thepresent invention the equilibrium concentration of drug may bedesignated as the drug concentration at 20 hours after delivery to a useenvironment. Thus, as used herein and in the claims, “equilibriumconcentration” means the drug concentration provided by a controlcomposition in in vitro dissolution experiments (such as PBS or MFDsolutions) after 20 hours, or the drug concentration provided by acontrol composition as measured using in vivo experiments after 20hours, where a sufficient amount of drug is in the control so that amaximum theoretical drug concentration provided by the control isgreater than the solubility of the drug. While in some cases the drugconcentration may still be changing after 20 hours, nevertheless acomparison of performance of compositions of the present inventionrelative to an “equilibrium concentration” provided by a controlcomposition measured after 20 hours in a use environment allows adetermination of whether compositions are within the scope of theinvention.

Alternatively, the compositions of the present invention provide adissolution AUC for a period of at least 90 minutes during the 1200minutes immediately following introduction to the use environment thatis 1.25-fold that of a dissolution AUC provided by a control compositioncomprising an equivalent quantity of drug in the solubility-improvedform but not containing the concentration-enhancing polymer. DissolutionAUC is the integration of a plot of the drug concentration versus timeover a specified time period. For purposes of determining whether acomposition or method is part of this invention, the dissolution AUC iscalculated over a time period as short as 90 minutes up to a time periodas long as 1200 minutes. The time period may be chosen for any timeperiod between the time of introduction into the use environment(time=0) and 1200 minutes following introduction into the useenvironment. Thus, acceptable time periods include, for example, (1)from the time of introduction into the use environment to 90 minutesfollowing introduction into the use environment; (2) from the time ofintroduction into the use environment to 180 minutes followingintroduction into the use environment; (3) from 90 minutes followingintroduction into the use environment to 180 minutes followingintroduction into the use environment; and (4) from 300 minutesfollowing introduction into the use environment to 1200 minutesfollowing introduction into the use environment. A composition or methodis part of this invention if it meets the dissolution AUC criterion forat least one acceptable time period. In vitro determinations of AUC canbe made by plotting drug concentration versus time after dissolving thedrug composition in, for example, PBS or MFD solution. Measurement ofthe AUC in vivo, where the use environment is, for example, the GItract, is more complicated. This requires sampling the GI fluid as afunction of time and thus is less preferred than the in vitrodissolution test or the in vivo relative bioavailability test.

In a preferred embodiment, the composition comprising the mixtureprovides enhanced relative bioavailability of the drug. In general,compositions or methods that are evaluated using one of the in vitrotest methods and found to be a part of the invention will perform wellin vivo as well. Bioavailability of drugs in the compositions or methodsof the present invention can be tested in vivo in animals, such asmammals and humans using conventional methods for making such adetermination. A convenient measure of in vivo bioavailability is the“relative bioavailability,” defined as the ratio of the plasma or serumAUC determined from a plot of the plasma or serum drug concentrationversus time measured for the composition or method of the presentinvention to the plasma or serum AUC of a control composition or methodthat is free of the concentration-enhancing polymer.

A composition of the present invention achieves a relativebioavailability that is at least 1.25. Preferably, the relativebioavailability provided by the composition of the present invention isat least 1.5, more preferably at least 2, and even more preferably atleast 3.

Compositions or methods of the invention pass either one or more invitro dissolution tests or the in vivo relative bioavailability test orboth in vitro and in vivo tests.

The concentration of dissolved drug in a dissolution test is typicallymeasured by sampling the test medium and analyzing for the dissolveddrug concentration. To avoid relatively large drug particulates whichwould give an erroneous determination, the test solution is eitherfiltered or centrifuged. “Dissolved drug” is typically taken as thatmaterial that either passes a 0.45 μm syringe filter or alternativelythe material that remains in the supernatant following centrifugation.Filtration can be conducted using a 13 mm, 0.45 μm polyvinylidinedifluoride syringe filter sold by Scientific Resources under thetrademark TITAN®. Centrifugation is typically carried out in apolypropylene microcentrifuge tube by centrifuging at about 13,000 G forabout 60 seconds. Other similar filtration or centrifugation methods canbe employed and useful results obtained. For example, using other typesof microfilters may yield values somewhat higher or lower (±10-40%) thanthat obtained with the filter specified above but will still allowidentification of preferred compositions. It will be appreciated by oneof ordinary skill that this definition of “dissolved drug” encompassesnot only monomeric solvated drug molecules but also a wide range ofspecies such as polymer drug assemblies that have submicron dimensionssuch as drug aggregates, aggregates of mixtures of polymer and drug,micelles, polymeric micelles, colloidal particles or nanocrystals,polymer/drug complexes, and other such drug-containing species that arepresent in the filtrate or supernatant in the specified dissolutiontest.

The Drug

The present invention is useful with any drug capable of beingformulated in a solubility-improved form. The term “drug” isconventional, denoting a compound having beneficial prophylactic and/ortherapeutic properties when administered to an animal, especiallyhumans. The drug does not need to be sparingly soluble in order tobenefit from this invention, although sparingly soluble drugs representa preferred class for use with the invention. Even a drug thatnonetheless exhibits appreciable solubility in the desired environmentof use can benefit from the increased solubility/bioavailability madepossible by this invention if the addition of theconcentration-enhancing polymer can reduce the size of the dose neededfor therapeutic efficacy or increase the rate of drug absorption incases where a rapid onset of the drug's effectiveness is desired.

The present invention finds particular utility when the drug is a“low-solubility drug”, meaning that the drug may be either“substantially water-insoluble,” which means that the drug has a minimumaqueous solubility at physiologically relevant pH (e.g., pH 1-8) of lessthan 0.01 mg/mL, “sparingly water-soluble,” that is, has an aqueoussolubility up to about 1 to 2 mg/mL, or even low to moderateaqueous-solubility, having an aqueous-solubility from about 1 mg/mL toas high as about 20 to 40 mg/mL. In general, it may be said that thedrug has a dose-to-aqueous solubility ratio greater than 10 mL, and moretypically greater than 100 mL, where the drug solubility is the minimumvalue observed in any physiologically relevant aqueous solution (e.g.,those with pH values between 1 and 8) including USP simulated gastricand intestinal buffers.

Preferred classes of drugs include, but are not limited to,antihypertensives, antianxiety agents, anticlotting agents,anticonvulsants, blood glucose-lowering agents, decongestants,antihistamines, antitussives, antineoplastics, beta blockers,anti-inflammatories, antipsychotic agents, cognitive enhancers,cholesterol-reducing agents, antiobesity agents, autoimmune disorderagents, anti-impotence agents, antibacterial and antifungal agents,hypnotic agents, anti-Parkinsonism agents, anti-Alzheimer's diseaseagents, antibiotics, anti-depressants, and antiviral agents.

Specific examples of the above and other classes of drugs andtherapeutic agents deliverable by the invention are set forth below, byway of example only. Each named drug should be understood to include theneutral form of the drug, pharmaceutically acceptable salts, as well asprodrugs. Specific examples of antihypertensives include prazosin,nifedipine, trimazosin and doxazosin; a specific example of anantianxiety agent is hydroxyzine; a specific example of a bloodglucose-lowering agent is glipizide; a specific example of ananti-impotence agent is sildenafil citrate; specific examples ofantineoplastics include chlorambucil, lomustine and echinomycin; aspecific example of an imidazole-type antineoplastic is tubulazole;specific examples of anti-inflammatory agents include betamethasone,prednisolone, aspirin, flurbiprofen and(+)-N-{4-[3-(4-fluorophenoxy)phenoxy]-2-cyclopenten-1-yl}-N-hydroxyurea;a specific example of a barbiturate is phenobarbital; specific examplesof antivirals include acyclovir, nelfinavir, and virazole; specificexamples of vitamins/nutritional agents include retinal and vitamin E;specific examples of beta blockers include timolol and nadolol; aspecific example of an emetic is apomorphine; specific examples of adiuretic include chlorthalidone and spironolactone; a specific exampleof an anticoagulant is dicumarol; specific examples of cardiotonicsinclude digoxin and digitoxin; specific examples of androgens include17-methyltestosterone and testosterone; a specific example of a mineralcorticoid is desoxycorticosterone; a specific example of a steroidalhypnotic/anesthetic is alfaxalone; specific examples of anabolic agentsinclude fluoxymesterone and methanstenolone; specific examples ofantidepression agents include sulpiride,[3,6-dimethyl-2-(2,4,6-trimethyl-phenoxy)-pyridin-4-yl]-(1-ethylpropyl)-amine,3,5-dimethyl-4-(3′-pentoxy)-2-(2′,4′,6′-trimethylphenoxy)pyridine,pyroxidine, fluoxetine, paroxetine, venlafaxine and sertraline; specificexamples of antibiotics include ampicillin and penicillin G; specificexamples of anti-infectives include benzalkonium chloride andchlorhexidine; specific examples of coronary vasodilators includenitroglycerin and mioflazine; a specific example of a hypnotic isetomidate; specific examples of carbonic anhydrase inhibitors includeacetazolamide and chlorzolamide; specific examples of antifungalsinclude econazole, terconazole, fluconazole, voriconazole, andgriseofulvin; a specific example of an antiprotozoal is metronidazole;specific examples of anthelmintic agents include thiabendazole andoxfendazole and morantel; specific examples of antihistamines includeastemizole, levocabastine, cetirizine, and cinnarizine; specificexamples of antipsychotics include ziprasidone, fluspirilene,risperidone and penfluridole; specific examples of gastrointestinalagents include loperamide and cisapride; specific examples of serotoninantagonists include ketanserin and mianserin; a specific example of ananesthetic is lidocaine; a specific example of a hypoglycemic agent isacetohexamide; a specific example of an anti-emetic is dimenhydrinate; aspecific example of an antibacterial is cotrimoxazole; a specificexample of a dopaminergic agent is L-DOPA; specific examples ofanti-Alzheimer's Disease agents are THA and donepezil; a specificexample of an anti-ulcer agent/H2 antagonist is famotidine; specificexamples of sedative/hypnotic agents include chlordiazepoxide andtriazolam; a specific example of a vasodilator is alprostadil; aspecific example of a platelet inhibitor is prostacyclin; specificexamples of ACE inhibitor/antihypertensive agents include enalaprilicacid and lisinopril; specific examples of tetracycline antibioticsinclude oxytetracycline and minocycline; specific examples of macrolideantibiotics include erythromycin, azithromycin, clarithromycin, andspiramycin; specific examples of glycogen phosphorylase inhibitorsinclude[R—(R*S*)]-5-chloro-N-(2-hydroxy-3-{methoxymethylamino}-3-oxo-1-(phenylmethyl)propyl-1H-indole-2-carboxamideand 5-chloro-1H-indole-2-carboxylic acid[(1S)-benzyl-(2R)-hydroxy-3-((3R,4S)-dihydroxy-pyrrolidin-1-yl-)-3-oxypropyl]amide.

Further examples of drugs deliverable by the invention are theglucose-lowering drug chlorpropamide, the anti-fungal fluconazole, theanti-hypercholesterolemic atorvastatin calcium, the antipsychoticthiothixene hydrochloride, the anxiolytics hydroxyzine hydrochloride anddoxepin hydrochloride, the anti-hypertensive amlodipine besylate, theanti-inflammatories piroxicam, valdicoxib, carprofen, and celicoxib, andthe antibiotics carbenicillin indanyl sodium, bacampicillinhydrochloride, troleandomycin, and doxycycline hyclate.

The drug is in a solubility-improved form, as defined above in theSummary of the Invention. However, other test media may be used todetermine if a drug is in a solubility-improved form, the appropriatemedium being different for each drug. Generally speaking, asolubility-improved drug form will provide a maximum concentration inthe test medium that is greater than the equilibrium concentrationprovided by a lower solubility form of the drug in the same test medium.In addition, since the maximum concentration provided by a drug in atest medium is always greater than or equal to the equilibriumconcentration provided by the same drug in the same test medium, a drugis considered to be in a solubility-improved form if the maximumconcentration provided by the drug in a test media is greater than themaximum concentration provided by a lower-solubility form of the drug.

One must use care when performing an experiment to determine if a drugis in a solubility-improved form, since, as discussed above, the rate atwhich a solubility-improved drug will convert to its lowest energy state(e.g., the lower solubility form) will vary greatly from drug to drugand from test medium to test medium. As discussed above, the rate atwhich the solubility-improved form of the drug will convert to itslowest energy form will vary greatly from drug to drug and will behighly dependent on the environment of use under which the drug foam isbeing evaluated. Therefore, it is desirable to evaluate the solubilityimprovement of a specific drug form in an in vitro test where the useenvironment can be carefully controlled. A drug in a solubility-improvedform will provide, at least temporarily, a dissolved drug concentrationin an in vitro test medium such as distilled water, or PBS or MFDsolution at physiologically relevant pH (e.g., from 1 to 8), that isgreater than the equilibrium concentration provided by the drug in alower solubility form. It has been found that distilled water at 37° C.is a convenient use environment for testing the solubility improvementof a drug form to determine whether a drug form is in asolubility-improved form.

In one aspect of the invention, the solubility-improved form of the drugis crystalline and is a highly soluble salt form of the drug. As usedherein, “highly soluble salt form” means that the drug is in a salt formthat provides in at least one in vitro test medium a maximumconcentration of the drug that is greater than the equilibriumconcentration provided by the lowest solubility form of the drug. Thedrug can be any pharmaceutically acceptable salt form of a basic,acidic, or zwitterionic drug that meets this criteria. Examples of saltforms for basic drugs include the hydrochloride, hydrobromide, chloride,bromide, acetate, iodide, mesylate, phosphate, maleate, citrate,sulfate, tartrate, lactate salts and the like. Examples of salt formsfor acidic drugs include the sodium, calcium, potassium, zinc,magnesium, lithium, aluminum, meglumine, diethanolamine, benzathine,choline, and procaine salts and the like. These salts can also be usedfor zwitterionic drugs.

Although essentially any salt form of a specific basic drug may providea higher drug concentration in a use environment relative to a knownlower solubility salt form, it is generally true that the free base orhydrochloride forms of a basic drug have low aqueous solubility relativeto other salt forms of the same drug. In addition, in the useenvironment of the GI tract of a mammal, the free base and hydrochlorideforms of a basic drug are commonly the drug forms with which solubilizeddrug will equilibrate. Thus, where the solubility-improved form of thedrug consists only of the basic drug, the solubility-improved form mustprovide improved drug concentration in a use environment relative to thefree base and hydrochloride forms of the drug. Preferred highly solublesalt forms are those salt forms that have aqueous solubility at least1.25-fold, preferably at least 2-fold, and more preferably at least5-fold, the aqueous solubility of the more soluble of the crystallinefree base and the crystalline hydrochloride salt forms. However, asdescribed below, when the solubility-improved form consists of drugcombined with a solubilizer, low-solubility salt foams or even the freebase form of the drug may be used.

It should further be noted with reference to low-solubility basic drugs,that they typically have higher solubility in the low pH gastricenvironment of the stomach relative to the solubility in the intestinesor colon that typically have a pH of about 6 to 8. Thus, even thoughdosing the lowest-solubility known drug form of such a drug to thegastric environment can create a high concentration of dissolved drug,such compositions and methods do not constitute part of this invention.

Preferably, when the solubility-improved form of the drug consists onlyof a crystalline salt form of a basic drug, the solubility-improved formof the drug provides a drug concentration in gastric fluid or simulatedgastric fluid that is greater than the maximum concentration of drugprovided by the free base or hydrochloride salt form of the drug in thesame fluid. In addition, when the solubility-improved form of the drugconsists only of a crystalline basic drug that is solubilized in thepresence of gastric fluid (i.e., is more soluble in gastric fluid thanin intestinal fluid), a composition comprising the solubility-improvedform of the basic drug and a concentration-enhancing polymer preferablyprovides improved relative bioavailability compared with a controlcomprising an equivalent amount of the same drug but in a low solubilityform (such as the hydrochloride salt form) and an equivalent amount ofconcentration-enhancing polymer.

An example of a basic drug having a crystalline highly soluble salt formis sertraline. At pH 3, sertraline lactate has a solubility of 256 mg/mL(expressed as the free base) in distilled water, whereas the HCl saltform has a solubility of only 3 mg/mL expressed as the free base. Afteroral delivery of sertraline lactate to simulated or actual gastricfluid, the drug exchanges the lactate counterion with chloride ionspresent in gastric fluid and precipitates or crystallizes as thechloride salt and/or free base until an equilibrium concentration isreached. The equilibrium concentration is lower than the maximumconcentration provided by sertraline lactate. The drug solubility alsodecreases as the pH of the surrounding fluid increases due to increasedconversion of the drug to the free base form which has a solubility of0.2 mg/mL at pH 7, which is lower than the solubility of the chloridesalt form. Thus, crystalline sertraline lactate is a solubility-improvedform relative to the crystalline hydrochloride salt and the crystallinefree base form of sertraline.

It should be noted that although distilled water may be used as a testmedium for evaluating whether a drug is in a solubility-improved form,it is not generally preferred for use as an in vitro environment of usesince its pH and chloride content does not reflect that present in atypical in vivo environment of use. Thus, the solubility-improved formpreferably provides an enhanced drug concentration relative to theequilibrium concentration in an in vitro use environment that has achloride content near that of the anticipated in vivo use environmentand a pH between about 6 and 8.

Alternatively, in another separate aspect of the invention, the drugexists in a high-energy crystalline form that has improved solubilityrelative to a low-energy crystalline form. It is known that some drugsmay crystallize into one of several different crystal forms. suchcrystal forms are often referred to as “polymorphs.” As used herein, “ahigh-energy crystalline form” means that the drug is in a crystal formwhich provides at least in an in vitro test medium a maximumconcentration of the drug that is greater than the equilibriumconcentration of the drug provided by another, lower-energy crystallineform.

An example of such a drug is the “A1” form of5-chloro-1H-indole-2-carboxylic acid[(1S)-benzyl-3-((3R,4S)-dihydroxypyrroldin-1-yl)-(2R)-hydroxy-3-oxpropyl]amide,which has a solubility in PBS of about 480 μg/mL while the “A2” form hasa solubility in PBS of only 87 μg/mL.

In yet another separate aspect of the invention, although the drug maybe capable of existing in either the amorphous or crystalline form, inthe composition it is in the amorphous form. The drug in its amorphousform provides in at least an in vitro test medium a maximumconcentration of the drug that is greater than the equilibriumconcentration of the drug provided by the drug in crystalline form. Anexample of such a drug is 5-chloro-1H-indole-2-carboxylic acid[(1S)-benzyl-3-((3R,4S)-dihydroxypyrroldin-1-yl-)-(2R)-hydroxy-3-oxypropyl]amide,the C_(max) of the amorphous form of which is 270 μg/mL, while theC_(max) of its crystalline form is only 160 μg/mL, both as measured inpH 6.5 MFD solution.

In yet another separate aspect of the invention, the solubility-improvedform of the drug is a mixture of the drug with a solubilizing agent. Thedrug/solubilizing agent mixture provides at least temporarily in atleast an in vitro test medium a maximum concentration of the drug thatis greater than the equilibrium concentration of the drug provided bythe drug without the solubilizing agent. An example of such adrug/solubilizing agent mixture is sertraline hydrochloride mixed withcitric acid, the equilibrium solubility of which is 28 mg/mL, ascompared to 3 mg/mL, for sertraline hydrochloride, both measured at pH3. Examples of solubilizing agents include surfactants; pH controlagents such as buffers, organic acids, organic acid salts, organic andinorganic bases, and organic and inorganic base salts; glycerides;partial glycerides; glyceride derivatives; polyoxyethylene andpolyoxypropylene ethers and their copolymers; sorbitan esters;polyoxyethylene sorbitan esters; carbonate salts; alkyl sulfonates; andcyclodextrins. In this aspect, the drug and solubilizing agent are bothpreferably solid.

There are a variety of factors to consider when choosing an appropriatesolubilizing agent for a drug. The solubilizing agent should notinteract adversely with the drug. In addition, the solubilizing agentshould be highly efficient, requiring minimal amounts to effect theimproved solubility. It is also desired that the solubilizing agent havea high solubility in the use environment. For acidic, basic, andzwitterionic drugs, organic acids and organic acid salts, organic andinorganic bases, and organic and inorganic base salts are known to beuseful solubilizing agents. It is generally desired that these compoundshave a high number of equivalents of acid or base per gram. In addition,it is generally desirable that the acid or base solubilizing agent bechosen such that the salt formed by the ionic form of the drug and thecorresponding conjugate acid or base of the solubilizing agent have ahigh solubility. The selection of solubilizing agent will therefore behighly dependent on the properties of the drug.

In yet another separate aspect of the invention, the solubility-improvedform of the drug is a solution or suspension of a drug substantiallydissolved or suspended in a liquid to a concentration that is at least10-fold an equilibrium concentration of the drug in the use environment.Examples of liquids suitable for this solubility-improved form of druginclude water-immiscible triglyceride vegetable oils such as saffloweroil, sesame oil, corn oil, castor oil, coconut oil, cottonseed oil,soybean oil, olive oil and the like; water-immiscible refined andsynthetic and semisynthetic oils such as mineral oil, the triglyceridesknown as MIGLYOLs®, including triglycerides of caprylic/capric acids andtriglycerides of caprylic/capric/linoleic acids, long-chain triglycerideoils such as triolein, other mixed-chain triglycerides which are liquidat room temperature, monoglycerides, diglycerides, and mixtures ofmono-, di-, and triglycerides; fatty acids and esters; water-misciblealcohols, glycerin and propyleneglycol; and water-misciblepolyethyleneglycols (PEGS) which are liquid at the temperature of theuse environment (which is typically about 35 to 40° C.), such asPEG-400. Examples of such materials that are commercially availableinclude corn oil, propylene glycol, CREMOPHOR RH-40 (polyoxy)-40hydrogenated castor oil), LABRAFIL M 2125 (linoleoyl polyoxyl-6glycerides), and 1944 (oleoyl polyoxyl-6 glycerides), ethanol, PEG 400,Polysorbate 80, glycerin, peppermint oil, soybean oil (long chaintriglyceride), sesame oil (long chain triglyceride), propylenecarbonate, and tocopheroyl TPGS. Other key commercial materials includeMIGLYOL 812 (caprylic/capric triglycerides), oleic acid, olive oil (longchain triglyceride), CAPMUL MCM (medium chain monoglyceride), CAPMULPG-8 (propylene glycol capyrlyl mono and diglycerides), CREMOPHOR EL(polyoxyl 35 castor oil), LABRASOL (caprylocaproyl polyoxyl-8glycerides), triacetin (acetyl triglyceride), MAISINE 35-1 (glycerylmonolinoleate), OLICINE (glyceryl mono oleate/linoleate), PECEOL(glyceryl monooleate), TRANSCUTOL P (diethylene glycol monoethylether),PLUROL Oleique CC (polyglyceryl-6 dioleate), LAUROGLYCOL 90 (propyleneglycol monolaureate), CAPRYOL 90 (propylene glycol monocaprylate),MYVACETS (acetylated monoglycerides), ARLACELS (sorbitan fatty acidester), PLURONICS (copolymers of propylene and ethylene oxide), BRIJ 30(polyoxylethylene 4 lauryl ether), GELUCIRE 44/14 (lauroyl polyoxyl-32glycerides), and GELUCIRE 33/01 (glycerol esters of fatty acids).Mixtures of these and other related materials are acceptable as long asthey are liquid at the temperature of the use environment which istypically about 35 to 40° C.

Concentration-Enhancing Polymers

Concentration-enhancing polymers suitable for use in the various aspectsof the present invention should be inert, in the sense that they do notchemically react with the drug in an adverse manner, and should have atleast some solubility in aqueous solution at physiologically relevantpHs (e.g. 1-8). Almost any neutral or ionizable polymer that has anaqueous-solublitity of at least 0.1 mg/mL over at least a portion of thepH range of 1-8 may be suitable.

A preferred class of concentration-enhancing polymers comprisesionizable and nonionizable cellulosic polymers (including those withether or ester or a mixture of ester and ether substituents andcopolymers thereof, including both so-called “enteric” and “non-enteric”polymers); and vinyl polymers and copolymers having substituents ofhydroxyl, alkylacyloxy, and cyclicamido. It is also preferred that theconcentration-enhancing polymers be “amphiphilic” in nature, meaningthat the polymer has hydrophobic and hydrophilic portions.

Amphiphilic and/or ionizable polymers are preferred because it isbelieved that such polymers tend to have relatively strong interactionswith the drug and may promote the formation of the various types ofpolymer/drug assemblies described previously. In addition, the repulsionof the like charges of the ionized groups of such polymers may serve tolimit the size of the polymer/drug assemblies to the nanometer orsubmicron scale. For example, while not wishing to be bound by aparticular theory, such polymer/drug assemblies may comprise hydrophobicdrug clusters surrounded by the concentration-enhancing polymer with thepolymer's hydrophobic regions turned inward towards the drug and thehydrophilic regions of the polymer turned outward toward the aqueousenvironment. Alternatively, depending on the specific chemical nature ofthe drug, the ionized functional groups of the polymer may associate,for example, via ion pairing or hydrogen bonds, with ionic or polargroups of the drug. In the case of ionizable polymers, the hydrophilicregions of the polymer would include the ionized functional groups. Suchdrug/concentration-enhancing polymer assemblies in solution may wellresemble charged polymeric micellar-like structures. In any case,regardless of the mechanism of action, the inventors have observed thatsuch amphiphilic polymers, particularly ionizable cellulosic polymerssuch as those listed below, have been shown to interact with drug so asto inhibit its crystallization.

Amphiphilic cellulosics may be prepared by substituting the cellulosicat any or all of the 3 hydroxyl substituents present on each sacchariderepeat unit with at least one relatively hydrophobic substituent.Hydrophobic substituents may be essentially any substituent that, ifsubstituted to a high enough level or degree of substitution, can renderthe cellulosic polymer essentially aqueous insoluble. Hydrophilicregions of the polymer can be either those portions that are relativelyunsubstituted, since the unsubstituted hydroxyls are themselvesrelatively hydrophilic, or those regions that are substituted withhydrophilic substituents. Examples of hydrophobic substitutents includeether-linked alkyl groups such as methyl, ethyl, propyl, butyl, etc.; orester-linked alkyl groups such as acetate, propionate, butyrate, etc.;and ether- and/or ester-linked aryl groups such as phenyl, benzoate, orphenylate. Hydrophilic groups include ether- or ester-linkednonionizable groups such as the hydroxy alkyl substituents hydroxyethyl, hydroxy propyl, and the alkyl ether groups such as ethoxyethoxyor methoxyethoxy. Particularly preferred hydrophilic substituents arethose that are ether- or ester-linked to the cellulose and, followingsubstitution have ionizable groups such as carboxylic acids,thiocarboxylic acids, substituted phenoxy groups, amines, phosphates orsulfonates. Specific substituents include, succinate, citrate,phthalate, trimellitate, hydroxyphenoxy, aminoethoxy, thiosuccinate,diethylaminoethoxy, trimethylamino ethoxy, sulphonate ethoxy, andphosphate ethoxy.

It should be noted that a polymer name such as “cellulose acetatephthalate” (CAP) refers to any of the family of cellulosic polymers thathave acetate and phthalate groups attached via ester linkages to asignificant fraction of the cellulosic polymer's hydroxyl groups.Generally, the degree of substitution of each substituent group canrange from 0.1 to 2.9 as long as the other criteria of the polymer aremet. “Degree of substitution” refers to the average number of the threehydroxyls per saccharide repeat unit on the cellulose chain that havebeen substituted. For example, if all of the hydroxyls on the cellulosechain have been phthalate substituted, the phthalate degree ofsubstitution is 3. Also included within each polymer family type arecellulosic polymers that have additional substituents added inrelatively small amounts that do not substantially alter the performanceof the polymer.

It should also be noted that in the polymer nomenclature herein,ether-linked substituents are recited prior to “cellulose” as the moietyattached to the ether group; for example, “ethylbenzoic acid cellulose”has ethoxybenzoic acid substituents. Analogously, ester-linkedsubstituents are recited after “cellulose” as the carboxylate; forexample, “cellulose phthalate” has one carboxylic acid of each phthalatemoiety ester-linked to the polymer and the other carboxylic acidunreacted.

Specific examples of cellulosic polymers that meet the definition ofamphiphilic, having hydrophilic and hydrophobic regions include polymerssuch as CAP and cellulose acetate trimellitate (CAT) where thecellulosic repeat units that have one or more acetate substituents arehydrophobic relative to those that have no acetate substituents or haveone or more ionized phthalate or trimellitate substituents; and polymerssuch as hydroxypropyl methyl cellulose (HPMC) or hydroxypropyl celluloseacetate (HPCA) where cellulosic repeat units that have relatively highnumbers of methoxy or acetate substituents relative to the unsubstitutedhydroxyl or hydroxypropyl substituents constitute hydrophobic regionsrelative to other repeat units on the polymer.

Non-cellulosic polymers that meet this definition of amphiphilicity arecopolymers of a relatively hydrophilic and a relatively hydrophobicmonomer. Examples include acrylate and methacrylate copolymers.Exemplary commercial grades of such copolymers include the EUDRAGITS,which are copolymers of methacrylates and acrylates manufactured by RohmTech Inc., of Malden, Mass.

Exemplary ionizable polymers that are at least partially ionized atphysiologically relevant pHs that may be used as theconcentration-enhancing polymer include: hydroxypropyl methyl celluloseacetate succinate, hydroxypropyl methyl cellulose succinate,hydroxypropyl methyl cellulose phthalate, hydroxyethyl methyl celluloseacetate succinate, hydroxyethyl methyl cellulose acetate phthalate,carboxyethyl cellulose, carboxymethyl cellulose, carboxymethyl ethylcellulose and carboxylic acid-functionalized polymethacrylates.

Exemplary non-ionizable polymers that may be used as theconcentration-enhancing polymers include: hydroxypropyl methyl celluloseacetate, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, methylcellulose, hydroxyethyl methyl cellulose, hydroxyethyl celluloseacetate, hydroxyethyl ethyl cellulose, polyvinyl alcohols that have atleast a portion of their repeat units in the unhydrolyzed (vinylacetate) form, polyvinyl alcohol polyvinyl acetate copolymers,polyethylene glycol, polyethylene glycol polypropylene glycolcopolymers, polyvinyl pyrrolidone, and polyethylene polyvinyl alcoholcopolymers and chitan.

One class of polymers which meets the requirements of the presentinvention includes cellulosic polymers with an ester- or ether-linkedaromatic substituent in which the polymer has a degree of substitutionof at least 0.1. Exemplary aromatic substituents include benzoate,phenoxy and ethoxy phenyl. For such aromatic-substituted polymers toalso have the requisite aqueous solubility, it is also desirable thatsufficient hydrophilic groups such as hydroxypropyl or carboxylic acidfunctional groups be attached to the polymer. Such carboxylic acidgroups can be ether-linked to the polymer as is the case for carboxyethyl groups, or they may be attached via ester linkages such as forsuccinate groups. The carboxylic acid and aromatic group can be combinedin a single substituent as is the case, for example for carboxylicacid-substituted aromatic groups that may be attached via ester linkageswhich include phthalate, trimellitate, the various isomers ofpyridinedicarboxylic acid, terephthalate, isophthalate andalkyl-substituted derivatives of these groups. Exemplary carboxylicacid-substituted aromatic groups that may be attached via ether linkagesinclude salicylic acid, alkoxybenzoic acids such as ethoxy benzoic acidor propoxybenzoic acid, the various isomers of alkoxyphthalic acid suchas ethoxyphthalic acid and ethoxyisophthalic acid, and the variousisomers of alkoxynicotinic acid such as ethcxynicotinic acid, andethoxypicolinic acid.

A particularly desirable subset of cellulosic ionizable polymers arethose that possess both a carboxylic acid functional aromaticsubstituent and an alkylate substituent. Exemplary polymers includecellulose acetate phthalate, methyl cellulose acetate phthalate, ethylcellulose acetate phthalate, hydroxypropyl cellulose acetate phthalate,hydroxypropyl methyl cellulose acetate phthalate, hydroxypropylcellulose acetate phthalate succinate, cellulose propionate phthalate,hydroxypropyl cellulose butyrate phthalate, cellulose acetatetrimellitate, methyl cellulose acetate trimellitate, ethyl celluloseacetate trimellitate, hydroxypropyl cellulose acetate trimellitate,hydroxypropyl methyl cellulose acetate trimellitate, hydroxypropylcellulose acetate trimellitate succinate, cellulose propionatetrimellitate, cellulose butyrate trimellitate, cellulose acetateterephthalate, cellulose acetate isophthalate, cellulose acetatepyridinedicarboxylate, salicylic acid cellulose acetate, hydroxypropylsalicylic acid cellulose acetate, ethylbenzoic acid cellulose acetate,hydroxypropyl ethylbenzoic acid cellulose acetate, ethyl phthalic acidcellulose acetate, ethyl nicotinic acid cellulose acetate, and ethylpicolinic acid cellulose acetate.

Another particularly desirable subset of cellulosic ionizable polymersare those that possess a non-aromatic carboxylate substituent. Exemplarypolymers include hydroxypropyl methyl cellulose acetate succinate,hydroxypropyl methyl cellulose succinate, hydroxypropyl celluloseacetate succinate, hydroxyethyl methyl cellulose acetate succinate,hydroxyethyl methyl cellulose succinate, and hydroxyethyl celluloseacetate succinate.

Even more preferred polymers are hydroxypropyl methyl cellulose acetatesuccinate, cellulose acetate phthalate, hydroxy propyl methyl cellulosephthalate, methyl cellulose acetate phthalate, hydroxypropyl celluloseacetate phthalate, cellulose acetate trimellitate, cellulose acetateterephthalate and cellulose acetate isophthalate. The most preferredpolymers are hydroxypropyl methyl cellulose acetate succinate,hydroxypropyl methyl cellulose phthalate, cellulose acetate phthalate,and cellulose acetate trimellitate.

While specific polymers have been discussed as being suitable for use inthe mixtures of the present invention, blends of such polymers may alsobe suitable. Thus the term “concentration-enhancing polymer” is intendedto include blends of polymers in addition to a single species ofpolymer.

Preparation of Compositions

The compositions of the present invention may be prepared by dry- orwet-mixing the drug or drug mixture with the concentration-enhancingpolymer to form the composition. Mixing processes include physicalprocessing as well as wet-granulation and coating processes. Anyconventional mixing method that does not substantially convert the drugand polymer to a molecular dispersion may be used.

For example, mixing methods include convective mixing, shear mixing, ordiffusive mixing. Convective mixing involves moving a relatively largemass of material from one part of a powder bed to another, by means ofblades or paddles, revolving screw, or an inversion of the powder bed.Shear mixing occurs when slip planes are formed in the material to bemixed. Diffusive mixing involves an exchange of position by singleparticles. These mixing processes can be performed using equipment inbatch or continuous mode. Tumbling mixers (e.g., twin-shell) arecommonly used equipment for batch processing. Continuous mixing can beused to improve composition uniformity.

Milling may also be employed to prepare the compositions of the presentinvention. Milling is the mechanical process of reducing the particlesize of solids (comminution). Because in some cases milling may altercrystalline structure and cause chemical changes for some materials,milling conditions are generally chosen which do not alter the physicalform of the drug in the sense that the drug and polymer are not mixed atthe molecular level to form a dispersion of polymer and drug. The mostcommon types of milling equipment are the rotary cutter, the hammer, theroller and fluid energy mills. Equipment choice depends on thecharacteristics of the ingredients in the drug form (e.g., soft,abrasive, or friable). Wet- or dry-milling techniques can be chosen forseveral of these processes, also depending on the characteristics of theingredients (e.g. drug stability in solvent). The milling process mayserve simultaneously as a mixing process if the feed materials areheterogeneous. Conventional mixing and milling processes suitable foruse in the present invention are discussed more fully in Lachman, etal., The Theory and Practice of Industrial Pharmacy (3d Ed. 1986). Thecomponents of the compositions of this invention may also be combined bydry- or wet-granulating processes as long as granulating conditions arechosen that do not transform a substantial portion of the drug into amolecular dispersion of polymer and drug.

In addition to the physical mixtures described above, the compositionsof the present invention may constitute any device or collection ofdevices that accomplishes the objective of delivering to the useenvironment both the drug in a solubility-improved form and theconcentration-enhancing polymer. Thus, in the case of oraladministration to a mammal, the dosage foam may constitute a layeredtablet wherein one or more layers comprise the solubility-improved formof the drug and one or more other layers comprise theconcentration-enhancing polymer. Alternatively, the dosage form may be acoated tablet wherein the tablet core comprises the solubility-improveddrug form and the coating comprises the concentration-enhancing polymer.In addition, the solubility-improved drug form and theconcentration-enhancing polymer may even be present in different dosageforms such as tablets or beads and may be administered simultaneously orseparately as long as both the solubility-improved drug form andconcentration-enhancing polymer are administered in such a way that thedrug and polymer can come into contact in the use environment. When thesolubility-improved drug form and the concentration-enhancing polymerare administered separately it is generally preferable to deliver thepolymer prior to the drug.

The amount of concentration-enhancing polymer relative to the amount ofdrug present in the mixtures of the present invention depends on thedrug and concentration-enhancing polymer and may vary widely from adrug-to-polymer weight ratio of 0.01 to 5. However, in most cases it ispreferred that the drug-to-polymer ratio is greater than 0.05 and lessthan 2.5 and often the enhancement in drug concentration or relativebioavailability is observed at drug-to-polymer ratios of 1 or less orfor some drugs even 0.2 or less. The minimum drug:polymer ratio thatyields satisfactory results varies from drug to drug and is bestdetermined in the in vitro and/or in vivo dissolution tests.

In general, to maximize the drug concentration or relativebioavailability of the drug, lower drug-to-polymer ratios are preferred.At low drug-to-polymer ratios, there is sufficientconcentration-enhancing polymer available in solution to ensure theinhibition of the precipitation or crystallization of drug from solutionand, thus, the average concentration of drug is much higher. For highdrug/polymer ratios, not enough concentration-enhancing polymer may bepresent in solution and drug precipitation or crystallization may occurmore readily. However, the amount of concentration-enhancing polymerthat can be used in a dosage form is often limited by the total massrequirements of the dosage form. For example, when oral dosing to ahuman is desired, at low drug/polymer ratios the total mass of drug andpolymer may be unacceptably large for delivery of the desired dose in asingle tablet or capsule. Thus, it is often necessary to usedrug/polymer ratios that are less than optimum in specific dosage formsto provide a sufficient drug dose in a dosage from that is small enoughto be easily delivered to a use environment.

Excipients and Dosage Forms

Although the key ingredients present in the compositions of the presentinvention are simply the drug to be delivered in its solubility-improvedform and the concentration-enhancing polymer(s), the inclusion of otherexcipients in the composition may be useful. These excipients may beutilized with the drug/polymer mixture in order to formulate the mixtureinto tablets, capsules, suspensions, powders for suspension, creams,transdermal patches, depots, and the like. Drug andconcentration-enhancing polymer can be added to other dosage formingredients in essentially any manner that does not substantially alterthe drug. In addition, as described above, the drug in itssolubility-improved form and the concentration-enhancing polymer may bemixed with excipients separately to form different beads, or layers, orcoatings, or cores or even separate dosage forms.

One very useful class of excipients is surfactants. Suitable surfactantsinclude fatty acid and alkyl sulfonates; commercial surfactants such asbenzethanium chloride (HYAMINE® 1622, available from Lonza, Inc.,Fairlawn, N.J.); DOCUSATE SODIUM (available from Mallinckrodt Spec.Chem., St. Louis, Mo.); polyoxyethylene sorbitan fatty acid esters(TWEEN®, available from ICI Americas Inc., Wilmington, Del.); LIPOSORB®P-20 (available from Lipochem Inc., Patterson N.J.); CAPMUL® POE-0(available from Abitec Corp., Janesville, Wis.), and natural surfactantssuch as sodium taurocholic acid,1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine, lecithin, and otherphospholipids and mono- and diglycerides. Such materials canadvantageously be employed to increase the rate of dissolution byfacilitating wetting, thereby increasing the maximum dissolvedconcentration, and also to inhibit crystallization or precipitation ofdrug by interacting with the dissolved drug by mechanisms such ascomplexation, formation of inclusion complexes, formation of micelles oradsorbing to the surface of solid drug, crystalline or amorphous. Thesesurfactants may comprise up to 5 wt % of the composition.

The addition of pH modifiers such as acids, bases, or buffers may alsobe beneficial, retarding the dissolution of the composition (e.g., acidssuch as citric acid or succinic acid when the polymer is anionic) or,alternatively, enhancing the rate of dissolution of the composition(e.g., bases such as sodium acetate or amines when the polymer isanionic).

Conventional matrix materials, complexing agents, solubilizers, fillers,disintegrating agents (disintegrants), or binders may also be added aspart of the composition itself or added by granulation via wet ormechanical or other means. These materials may comprise up to 90 wt % ofthe composition.

Examples of matrix materials, fillers, or diluents include lactose,mannitol, xylitol, microcrystalline cellulose, dibasic calciumdiphosphate, and starch.

Examples of disintegrants include sodium starch glycolate, sodiumalginate, carboxy methyl cellulose sodium, methyl cellulose, andcroscarmellose sodium.

Examples of binders include methyl cellulose, microcrystallinecellulose, starch, and gums such as guar gum, and tragacanth.

Examples of lubricants include magnesium stearate and calcium stearate.

Other conventional form excipients may be employed in the compositionsof this invention, including those excipients well-known in the art.Generally, excipients such as pigments, lubricants, flavorants, and soforth may be used for customary purposes and in typical amounts withoutadversely affecting the properties of the compositions. These excipientsmay be utilized in order to formulate the composition into tablets,capsules, suspensions, powders for suspension, creams, transdermalpatches, and the like.

Compositions of this invention may be used in a wide variety of dosageforms for administration of drugs. Exemplary dosage forms are powders orgranules that may be taken orally either dry or reconstituted byaddition of water to form a paste, slurry, suspension or solution;tablets; capsules; multiparticulates; and pills. Various additives maybe mixed, ground, or granulated with the compositions of this inventionto form a material suitable for the above dosage forms.

In some cases, the overall dosage form or particles, granules or beadsthat make up the dosage form may have superior performance if coatedwith an enteric polymer to prevent or retard dissolution until thedosage form leaves the stomach. Exemplary enteric coating materialsinclude HPMCAS, HPMCP, CAP, CAT, carboxylic acid-functionalizedpolymethacrylates, and carboxylic acid-functionalized polyacrylate.

Compositions of this invention may be administered in a controlledrelease dosage form. In one such dosage form, the composition of thedrug in the solubility-improved form and concentration-enhancing polymeris incorporated into an erodible polymeric matrix device. By an erodiblematrix is meant aqueous-erodible or water-swellable or aqueous-solublein the sense of being either erodible or swellable or dissolvable inpure water or requiring the presence of an acid or base to ionize thepolymeric matrix sufficiently to cause erosion or dissolution. Whencontacted with the aqueous environment of use, the erodible polymericmatrix imbibes water and forms an aqueous-swollen gel or “matrix” thatentraps the mixture of solubility-improved drug andconcentration-enhancing polymer. The aqueous-swollen matrix graduallyerodes, swells, disintegrates or dissolves in the environment of use,thereby controlling the release of the drug mixture to the environmentof use.

Alternatively, the compositions of the present invention may beadministered by or incorporated into a non-erodible matrix device.

Alternatively, the drug mixture of the invention may be delivered usinga coated osmotic controlled release dosage form. This dosage form hastwo components: (a) the core which contains an osmotic agent and thedrug in a solubility-improved form and the concentration-enhancingpolymer either mixed or in separate regions of the core; and (b) anon-dissolving and non-eroding coating surrounding the core, the coatingcontrolling the influx of water to the core from an aqueous environmentof use so as to cause drug release by extrusion of some or all of thecore to the environment of use. The osmotic agent contained in the coreof this device may be an aqueous-swellable hydrophilic polymer, osmogen,or osmagent. The coating is preferably polymeric, aqueous-permeable, andhas at least one delivery port.

Alternatively, the drug mixture of the invention may be delivered via acoated hydrogel controlled release dosage form having three components:(a) a composition containing the drug in the solubility-improved form,(b) a water-swellable composition wherein the water-swellablecomposition is in a separate region within a core formed by thedrug-containing composition and the water-swellable composition, and (c)a coating around the core that is water-permeable, water-insoluble, andhas a least one delivery port therethrough. In use, the core imbibeswater through the coating, swelling the water-swellable composition andincreasing the pressure within the core, and fluidizing thedrug-containing composition. Because the coating remains intact, thedrug-containing composition is extruded out of the delivery port into anenvironment of use. The concentration-enhancing polymer may be deliveredin a separate dosage form, may be included in the drug-containingcomposition or may constitute all or part of a coating applied to thedosage form.

When the solubility-improved drug form is a solution or suspension ofthe drug in an aqueous or organic liquid the composition can bedelivered via soft gelatin or hard gelatin capsules, which are known andwell understood in the art. These dosage forms comprise a water-solublesoft or hard gelatin exterior shell that encapsulates a vehicle in whicha drug has been dissolved and/or suspended. Examples of vehicles usedfor this purpose are discussed above. Here, the concentration-enhancingpolymer can be dissolved or suspended in the aqueous or organic liquid.Alternatively, the soft or hard gelatin exterior shell can be coatedwith or made from the concentration-enhancing polymer.

Alternatively, the compositions of the present invention may beco-administered, meaning that the drug in its solubility-improved formcan be administered separately from, but within the same general timeframe as, the concentration-enhancing polymer. Thus, a drug in asolubility-improved form can, for example, be administered in its owndosage form which is taken at approximately the same time as theconcentration-enhancing polymer which is in a separate dosage form. Ifadministered separately, it is generally preferred to administer boththe drug in its solubility-improved form and the concentration-enhancingpolymer within 60 minutes of each other, so that the two are presenttogether in the environment of use. When not administeredsimultaneously, the concentration-enhancing polymer is preferablyadministered prior to the solubility-improved form of the drug.

In addition to the above additives or excipients, use of anyconventional materials and procedures for preparation of suitable dosageforms using the compositions of this invention known by those skilled inthe art are potentially useful.

Other features and embodiments of the invention will become apparentfrom the following examples which are given for illustration of theinvention rather than for limiting its intended scope.

Examples 1-3

These examples demonstrate a composition comprising a mixture of anamorphous drug and concentration-enhancing polymer, as well as an invitro dissolution test known as the “microcentrifuge” method. Thismethod was used to test the dissolution of mixtures of the MF grade ofhydroxypropyl methyl cellulose acetate succinate (HPMCAS-MF, containing23.4% methoxyl, 7.2% hydroxypropoxy, 9.4% acetyl, 11.0% succinoyl,average molecular weight of 10,000 to 20,000, manufactured by Shin Etsu)and amorphous 5-chloro-1H-indole-2-carboxylic acid[(1S)-benzyl-3-((3R,4S)-dihydroxypyrroldin-1-yl-)-(2R)-hydroxy-3-oxypropyl]amide(a glycogen phosphorylase inhibitor) (Drug 1). The maximum concentrationof Drug 1, C_(max), for the amorphous form in pH 6.5 MFD solution is 270μg/mL, while the C_(max) of the crystalline form is only 160 μg/mL.

Amorphous drug (here the solubility-improved form) was prepared byadding 10 g of Drug 1 to 118 g of acetone and 6.2 g of water. Solventwas rapidly removed from this solution by spray-drying. Duringspray-drying, the drug solution was placed in a pressure vessel thatdelivered the drug solution at a controlled rate to a commercial spraydryer (Mobile Minor Hi-Tec for Non-Aqueous Feed Spray Dryer,manufactured by Niro A/S, Soburg, Denmark). The Niro spray dryerconsists of a two-fluid nozzle atomizer that fits into the top of adrying chamber. Nitrogen atomizing gas was delivered to the nozzle at2.7 bar and the drug solution was delivered at a flow rate of 197 g/min.Drying gas (nitrogen heated to 197° C.) was delivered to the dryingchamber through an inlet duct that surrounds the two-fluid nozzle. Thespray-dried material exited the chamber with the drying gas throughtransport ducts and passed into a cyclone. At the top of the cyclone, anexhaust vent allowed the nitrogen and evaporated solvent to escape. Thespray-dried material was collected in a canister. The material was adry, white, substantially amorphous powder. The yield of amorphous drugwas 43%.

In a 37° C. temperature-controlled box, 3.6 mg of amorphous Drug 1 wasaccurately weighed into eight empty microcentrifuge tubes(polypropylene, Sorenson Bioscience, Inc.). The theoretical maximumsupersaturated concentration of compound in solution was 2000 μg/mL (3.6mg drug [1000 μg/1 mg]/1.8 mL=2000 μg/mL). (The theoretical maximumsupersaturated concentration which is abbreviated as theoretical C_(max)represents the concentration if all of the compound was dissolved.)Tests were performed in duplicate.

Control 1 consisted only of amorphous Drug 1 in Tubes 1 and 2. ForExample 1, 1.2 mg of HPMCAS-MF was added to Tubes 3 and 4. For Example2, 3.6 mg of HPMCAS-MF was added to Tubes 5 and 6. For Example 3, 10.8mg of HPMCAS-MF was added to Tubes 7 and 8. These four groups of samplesrepresented a Control 1 of amorphous Drug 1 and compositions 1, 2 and 3having drug:polymer ratios of 3:1, 1:1, and 1:3, respectively.

At time equal to 0, 1.8 mL of a 37° C. PBS solution (8.2 mM NaCl, 1.1 mMNa₂HPO₄, 4.7 mM KH₂PO₄, pH 6.5, 290 mOsm/kg) was added to each tube. Thecentrifuge tubes were closed and a timer was started. The tubes werethen mixed continuously at the highest speed of a Fisher Vortex Genie 2mixer for 60 seconds. The tubes were then transferred to a centrifuge(Marathon, Model Micro A), and then centrifuged at 13,000 G for 60seconds. At 4 minutes, a 50-μL sample was removed from the solids-freesupernatant in the centrifuge tubes via pipette. Solids in thecentrifuge tube were resuspended by mixing the sample continuously onthe vortex mixer for 30 seconds. The centrifuge tube was returned to thecentrifuge and allowed to stand undisturbed until the next sample wastaken. Each sample was centrifuged, sampled, and resuspended asdescribed above. Each sample was diluted by adding 50 AL of supernatantto 250 AL of methanol, and the concentration of the compound wasdetermined by high-performance liquid chromatography (HPLC) (HewlettPackard 1100, Zorbax SB C18 column, 35% acetonitrile (ACN)/65% H₂O,absorbance measured at 297 nm with a diode array spectrophotometer).

Samples were taken after 4, 10, 20, 40, 90, 180, and 1200 minutes asdescribed above, analyzed, and compound concentrations were calculated.The data are summarized in Table 1.1. Each of Examples 1-3 sustained theconcentration of drug in solution above the equilibrium concentrationprovided by Control 1 for greater than 20 hours (1200 minutes).

TABLE 1.1 [Drug 1] (μg/mL) 1 2 3 Time Control 1 (3:1 (1:1 (1:3 (mins)(Drug Alone) Drug 1:HPMCAS-MF) Drug 1:HPMCAS-MF) Drug 1:HPMCAS-MF) 4 574714 754 998 10 507 736 739 1032 20 286 695 835 1064 40 217 690 845 113290 187 728 897 1184 180 208 683 917 1301 1200 203 440 626 1377

The maximum concentration of drug reached (C_(max)), the dissolutionarea under a curve plotting the concentration of Drug 1 versus time from0 to 90 minutes (AUC₉₀), and the concentration after 20 hours, or 1200minutes, (C₁₂₀₀) were calculated and are reported in Table 1.2, togetherwith the theoretical C_(max). The theoretical C_(max) is the drugconcentration that would be obtained if all of Drug 1 was dissolved.That is, the total mass of active drug dosed to the test solution in μgdivided by the total volume of the test solution in mL. As is apparent,the C_(max) for Examples 1, 2 and 3 was 1.28-fold, 1.6-fold and 2.4-foldthat of amorphous drug alone (Control 1), while the AUC₉₀ for Examples1, 2 and 3 was 2.7-, 3.0-, and 4.2-fold that of the amorphous drug alone(Control 1).

TABLE 1.2 Theoretical C_(max) AUC₉₀ C₁₂₀₀ C_(max) Example (μg/mL)(min*μg/mL) (μg/mL) (μg/mL) Control 1 574 23,500 203 2000 (Drug 1 only)1 736 62,200 440 2000 (3:1 Drug 1 HPMCAS-MF) 2 917 74,200 626 2000 (1:1Drug 1 HPMCAS-MF) 3 1377 98,400 1377 2000 (1:3 Drug 1 HPMCAS-MF)

Example 4

This example demonstrates another composition of amorphous Drug 1 and aconcentration-enhancing polymer. Amorphous Drug 1 was prepared asdescribed in Example 1, and dissolution was measured for an oral powderfor constitution (OPC) suspension in an in vitro test known as the“gastric buffer to PBS transfer test.” The test mimics oraladministration of an OPC dosage form by exposure to a small volume ofacidic fluid (gastric buffer) for 30 minutes followed by exposure to PBSsolution (intestinal buffer).

For these tests, 40 mL of gastric buffer (0.084 M HCl, 0.058 M NaCl, 7.0atm, pH 1.2) was added to a 500-mL dissoette flask at 37° C. Control 2consisted of 0.6 g of amorphous Drug 1. Example 4 consisted of 0.6 g ofamorphous Drug 1 and 1.8 g of HPMCAS-MF. The constituents of Control 2and Example 4 were weighed into OPC bottles, respectively, and 15 mL of2 wt % Tween 80 was added to each bottle. Each solution was mixed for 2minutes. Deionized water (105 mL) was added to each OPC bottle, eachbottle was inverted twice, and the contents were added to respectivedissoette flasks. Each OPC bottle was rinsed into the respectivedissoette flask twice, each time using 60 mL of deionized water. Eachdissoette flask was stirred at 100 rpm for 30 minutes; a sample wastaken from each after 25 minutes. After 30 minutes of stirring, 0.55 mLof 10% NaOH and 200 mL of 2.5×PBS (PBS solution with 2.5 times thestandard buffer salt concentration) were added to each dissoette flask.The pH of the solution within each flask was adjusted to 6.5 with 10%NaOH.

Samples were taken at 4, 10, 20, 40, 90, 180, and 1200 minutes followingadjustment of the pH to 6.5. This was done by removing four drops fromeach dissoette flask and placing the drops in a respectivemicrocentrifuge tube. Samples were centrifuged for 1 minute at 13,000 G.Supernatant (50 μL) was removed and added to 250 μL of Methanol in anHPLC vial. Drug concentrations were measured using HPLC. The results areshown in Table 2.1.

TABLE 2.1 [Drug 1] (μg/mL) Time Control 2: Example 4 (mins) (Drug 1only) (1:2 Drug 1:HPMCAS-MF) 0 720 427 4 359 857 10 357 880 20 325 89340 291 886 90 263 923 180 251 765 1200 237 528

The C_(max) the AUC₁₈₀ (AUC calculated from 0 to 180 minutes), the C₁₂₀₀and the theoretical C_(max) are shown in Table 2.2.

TABLE 2.2 C_(max) AUC₁₈₀ C₁₂₀₀ Theoretical Example (μg/mL) (min*μg/mL)(μg/mL) (μg/mL) Control 2 720 50,800 237 1250 (Drug 1 only) Example 4923 155,600 528 1250 (1:2 Drug 1:HPMCAS-MF)

As the data show, C_(max) for Example 4 consisting of the amorphous drugwith HPMCAS-MF polymer was 1.28-fold that of Control 2, consisting ofthe amorphous drug alone, while the AUC₁₈₀ for Example 4 was 3-fold theAUC₁₈₀ for the Control 2.

Examples 5-9

These examples demonstrate compositions of amorphous Drug 1 mixed withvarying ratios of a concentration-enhancing polymer. Amorphous Drug 1(15 mg) was added to microcentrifuge tubes containing 1.5 mL of PBSsolution and varying concentrations of HPMCAS-MF. Dissolutionperformance was measured at 37° C. using the microcentrifuge methoddescribed in Example 1. Drug concentration was measured at 1.5 hours andat 20 hours for each polymer concentration. The results are shown inTable 3.

TABLE 3 Drug 1: [Drug] [Drug] HPMCAS-MF 1.5 hr. 20 hr Example Ratio(w:w) (μg/mL) (μg/mL) Control 3 No HPMCAS-MF 224 196 5 20:1  447 289 610:1  487 293 7 5:1 4928 1550 8 1:1 7453 5431 9 1:2 8099 7451

The data in Table 3 show that even at low polymer concentrations, someconcentration-enhancement was observed. However, the effect increasedwith decreasing drug:polymer weight ratio. This shows that to maximizethe concentration enhancement, a sufficient amount of polymer must bepresent in the composition.

Examples 10-11

These examples demonstrate compositions of a drug in a highly solublesalt form (the solubility-improved form) and a concentration-enhancingpolymer. As discussed in the section describing solubility-improveddrugs, sertraline lactate (Drug 2) is a soluble salt form of theanti-depressant drug sertraline. The solubility of sertraline lactate is256 mg/mL (calculated using the molecular weight of the free base whichis 306 g/mol), while the solubility of the hydrochloride salt is only 3mg/mL (calculated using the molecular weight of the free base), bothmeasured at pH 3.

For these tests, 1.8 mg sertraline lactate was added to 0.9 mL HPLCwater in each of six microcentrifuge tubes. For Control 4, 0.9 mL 2×PBS(PBS solution with 2 times the standard buffer salt concentration),adjusted to pH 8.0, was added to Tubes 1 and 2. For Example 10, 0.9 mL2×PBS (pH 8.0) containing 3.6 mg of HPMCAS-MF was added to Tubes 3 and4. For Example 11, 0.9 mL 2×PBS (pH 8.0) containing 3.6 mg of CAT wasadded to Tubes 5 and 6. Control 4 did not containconcentration-enhancing polymer.

Dissolution performance was measured at 37° C. using the microcentrifugemethod described in Example 1. Samples were taken after 4, 10, 20, 40,90, and 180 minutes as described in Example 1. Samples were diluted in35% H₂O/65% ACN (vol./vol.), and analyzed by HPLC. The mobile phase was35 vol. % 0.025 M triethylamine with 0.05M acetic acid in HPLC water inACN. The analytical column used was a Phenomenex ODS 20, and the drugconcentration was determined using diode array detection at 230 nm.Results of the microcentrifuge test are shown in Table 4.1.

TABLE 4.1 [Drug 2] (μg/mL) Control 4 Example 10 Example 11 Time (Drug 2(1:2 (1:2 (mins) only) Drug 2:HPMCAS-MF) Drug 2:CAT) 4 101 617 456 10 89550 376 20 72 459 321 40 67 413 286 90 63 373 283 180 60 341 245

These data show that for the compositions containing aconcentration-enhancing polymer the maximum concentration of Drug 2 was4.5-fold to 6.1-fold that of Control 4.

TABLE 4.2 Theoretical C_(max) AUC₁₈₀ C_(max) Example (μg/mL) (min*μg/mL)(μg/mL) Control 4 101 11,700 1000 (Drug 2 only) 10 617 70,300 1000 (1:2Drug 2:HPMCAS-MF) 11 456 50,900 1000 (1:1 Drug 2:CAT)

Table 4.2 shows the AUC₁₈₀ for the composition containing HPMCAS-MF was6.0-fold that of the Control 4, and the AUC₁₈₀ for the compositioncontaining CAT was 4.4-fold that of Control 4.

Examples 12-14

These examples demonstrate a composition comprising a drug in a highlysoluble salt form (here the solubility-improved form) and aconcentration-enhancing polymer. Ziprasidone mesylate (Drug 3) is thesoluble salt form of the antipsychotic drug ziprasidone. For thesetests, 0.5 mg drug was added to each of 8 microcentrifuge tubes. ForControl 5, no concentration-enhancing polymer was added to Tubes 1 and2. For Example 12, 1.0 mg of CAT was added to Tubes 3 and 4. For Example13, 1.0 mg of CAP (NF grade from Eastman Fine Chemical of Kingsport,Tenn.) was added to Tubes 5 and 6. For Example 14, 1.0 mg HPMCP(NF gradefrom Eastman Chemical Company) was added to Tubes 7 and 8.

Dissolution performance was measured at 37° C. using the microcentrifugemethod described in Example 1. For each test, 0.616 mg of Drug 3 wasadded to the microcentrifuge tube. At time 0, 1.8 mL PBS was added toeach of the tubes. Drug concentration was measured using HPLC, with amobile phase of 60 vol. % 0.02 M KH₂PO₄, pH 3.0 in ACN, and diode arraydetection at 254 nm. Results of the dissolution tests are shown in Table5.1.

TABLE 5.1 [Drug 3] (μg/mL) Control 5 Example 12 Example 13 Example 14Time (Drug 3 (1:2 (1:2 (1:2 (mins) only) Drug 3:CAT) Drug 3:CAP) Drug3:HPMCP) 10 3 23 18 22 20 11 23 21 18 40 6 11 22 6 90 7 6 25 6 180 1 523 12

Table 5.2 reports C_(max), AUC₁₈₀ and theoretical C_(max). The C_(max)of Examples 12-14 were 2.0-fold to 2.3-fold that of Control 5, while theAUC₁₈₀ for Examples 12-13 were 1.6-fold to 4.0-fold that of Control 5.

TABLE 5.2 Theoretical C_(max) AUC₁₈₀ C_(max) Example (μg/mL) (min*μg/mL)(μg/mL) Control 5 11 1000 342 (Drug 3 only) 12 23 1600 342 (1:2 Drug3:CAT) 13 25 4000 342 (1:2 Drug 3:CAP) 14 22 1600 342 (1:2 Drug 3:HPMCP)

Examples 15-16

These examples demonstrate compositions of a drug in a high-energycrystalline state (here the solubility-improved form) and aconcentration-enhancing polymer. The mesylate salt of the epidermalgrowth factor receptor tyrosine kinase inhibitor (EGFR-TK inhibitor)[6,7-Bis(2-methoxy-ethoxy)-quinazolin-4-yl]-(3-ethynyl-phenyl)amine(Drug 4) has been isolated in various polymorphs with differentsolubilities. The “A” form, for example, has a solubility of 102 μgA/mLin water, while the “C” form has a solubility of 28 μA/mL. Thesepolymorphs are metastable forms that can interconvert rapidly with morestable forms to reach a lower equilibrium concentration in theenvironment of use. In these examples, the “A” polymorph was studied.

For these tests, 2.5 mg of polymorph “A” of Drug 4 was added to each of6 microcentrifuge tubes. For Control 6, no concentration-enhancingpolymer was added to Tubes 1 and 2. For Example 15, 1.2 mg of HPMCAS-MFwas added to Tubes 3 and 4. For Example 16, 1.2 mg of HPMCP was added totubes 5 and 6.

Dissolution performance was measured at 37° C. using the microcentrifugemethod. At time 0, 1.8 mL PBS was added to tubes 1 to 6. Drugconcentration was measured using HPLC. The mobile phase was a 55/45(v/v) mixture of 0.2 wt % trifluoroacetic acid adjusted to pH 3.0 withammonium hydroxide in HPLC water and 85/15 (v/v) acetronitrile/isopropylalcohol. The analytical column used was an Inertsil C8, and the drugconcentration was determined using diode array detection at 252 nm.Results of the dissolution tests are shown in Table 6.1.

TABLE 6.1 [Drug 4] (μg/mL) Control 6 Example 15 Example 16 Time (Drug 42.1:1 2.1:1 (mins) only) (Drug 4:HPMCAS-MF) (Drug 4:HPMCP) 4 11 287 16410 18 113 41 20 21 34 32 40 14 36 44 90 18 29 49 1200 10 32 121

Table 6.2 shows the C_(max) for the composition containing HPMCAS-MF(Example 15) was 13.7-fold that of Control 6, while the AUC₉₀ was3.2-fold that of Control 6. The C_(max) for the composition containingHPMCP (Example 16) was 7.8-fold that of Control 6, while the AUC₉₀ was2.9-fold that of Control 6.

TABLE 6.2 Theoretical C_(max) AUC₉₀ C₁₂₀₀ C_(max) Example (μg/mL)(min*μg/mL) (μg/mL) (μg/mL) Control 6 21 1500 10 1391 (Drug 4 only) 15287 4800 32 1391 (2.1:1 Drug 4:HPMCAS-MF) 16 164 4400 121 1391 (2.1:1Drug 4:HPMCP)

Example 17

This example demonstrates a solubilizing agent mixed with the drug asthe solubility-improved form of the drug. The solubility of sertralineHCl (Drug 5) at 37° C. was determined at pH 3.1 in water (adjusted to pH3.1 with acetic acid) and in saturated citric acid at the same pH. Asshown in Table 7.1, the solubility of Drug 5 was dramatically increasedin the presence of citric acid, giving a solubility-improvement factorof 9.3. Thus, citric acid is an excellent solubilizing agent for Drug 5.

TABLE 7.1 Sertraline HCl Drug Form (mg/mL) Drug 5 3 Drug 5 in saturated28 citric acid

For Example 17, a solution was prepared containing 1,000 μg/mL Drug 5,500 μg/mL citric acid, and 1,000 μg/mL HPMCAS-MF in phosphate buffer (pH7.9). For Control 7, solution containing no concentration-enhancingpolymer was prepared.

Dissolution performance was measured at 37° C. using the microcentrifugemethod described in Example 1. Samples were taken at 15, 30, 60, 120,and 240 minutes as described in Example 1 and analyzed for Drug 5 usingthe same procedure described in Example 10. The results of these testsare shown in Table 7.2, with various calculated values reported in Table7.3.

TABLE 7.2 Time [Drug 5] Example (min) (μg/mL) 17 15 106 30 94 60 55 12059 240 58 Control 7 5 — 15 64 30 52 60 55 120 52 240 39

TABLE 7.3 Theoretical C_(max) AUC₁₂₀ C_(max) Example (μg/mL) (min*μg/mL)(μg/mL) Example 17 106 8700 1000 Control 7 64 6500 1000

These data show that the addition of the concentration-enhancing polymerHPMCAS resulted in a C_(max) for Example 17 that was 1.7-fold that ofControl 7. In addition, the AUC₁₂₀ was 1.3-fold than that of Control 7.

Example 18

This example demonstrates the use of the present invention in vivo.Aqueous solutions of a soluble drug form and a concentration-enhancingpolymer were administered to dogs. The solubility-improved drug form wasthe mesylate salt of the drug4-[3-[4-(2-methylimidazol-1-yl)phenylthio]phenyl]-3,4,5,6-tetrahydro-2H-pyran-4-carboxamidehemifumarate (Drug 6). For this drug, the solubility of thehydrochloride salt is 0.37 mgA/mL at pH 4, while the solubility of themesylate salt (the solubility-improved form of the drug) is 3.7 mgA/mLat pH 4. The solubility of both of these drug forms decreases withincreasing pH. At pH 7, the solubility of the hydrochloride salt is0.0009 mgA/mL, and the solubility of the mesylate salt is 0.0042 mgA/mL.Ideally, it would be useful to maintain the higher solubility of thesolubility-improved drug form in gastric fluid, and also to maintain thedrug concentration as the pH increases in intestinal solution.

Example 18 was prepared as a suspension containing 15 mgA Drug 6 in a1:10 (w/w) Drug 6/HPMCAS-LF physical mixture. Control 8 contained noHPMCAS. The suspension compositions for Example 18 and Control 8 arepresented in Table 8.1.

TABLE 8.1 Example 18 Control 8 Component (g) (g) Drug 6 (0.814 potency)0.246 0.246 HPMCAS 2.000 — Sterile water 40 40 pH 2.9 4.1

After an overnight fast, dogs were dosed with 20 mL of the suspension,followed immediately by a 10 cc flush of air via a surgically-placedaccess port, directly into the ascending colon. Blood (5 mL) wascollected from the jugular vein pre-dosing and at hours 0.25, 0.5, 1, 2,4, 6, 8, 12 and 24 post-dosing.

Plasma concentrations of Drug 6 in standards, controls and study sampleswere determined by LC/MS analysis. Aliquots of 100 μL of plasma fromsamples, standards and controls were added into the appropriate wells ofa 96-well plate followed by addition of 5 μL of internal standard (IS),4-[(5-Fluoro-3-[4-(2-methylimidazol-1-yl)benzyloxy]phenyl]-3,4,5,6-tetrahydro-2H-pyran-4-carboxamide(10 μg/mL in 50/50 acetonitrile/water) into each well; followed by theaddition of 100 μL acetonitrile into each well. After vortexing andcentrifugation (5 minutes at 1730 G), the supernatant of each well wastransferred to a new well of a 96-well plate and 20 μL was injected ontoa LC/MS system. The reverse-phase HPLC system consisted of a Waters C18Symmetry® analytical column (2.1 mm×150 mm). The mobile phase solventswere: solvent A=5 mM ammonium acetate, with 1% isopropyl alcohol perliter of mobile phase and solvent B=acetonitrile, with 1% isopropylalcohol per liter of mobile phase. The gradient was 0-3.0 minutes, 100%A to 0% A, at 3.1 minute switch back to 100% A, at a flow rate of 0.5mL/min. Retention times for Drug 6 and IS were both approximately 2.6minutes. Detection was accomplished by a SCIEX PE API-150 massspectrometer equipped with a Turbo IonSpray interface. The positive ionswere monitored for the quantification of Drug 6 (m/z 394.1) and IS (m/z410.3), respectively. The ratio of peak area responses of Drug 6relative to the internal standard was used to construct a standard curveusing a linear least square regression with a 1/x2 weighting. The lowerlimit of quantification (LLOQ) and upper limit of quantification (ULOQ)of the plasma assay were 0.01 and 5 μg/mL, respectively. The performanceof the assay was monitored by the inclusion of quality control samplesprepared in dog plasma.

Pharmacokinetic data are presented in Table 8.2, where C_(max) is themaximum observed plasma Drug 6 concentration, averaged over the numberof dogs dosed with each form. AUC₁₂₀₀ is the average area under theplasma Drug 6 concentration vs. time curve from 0 to 24 hours (1200minutes).

TABLE 8.2 Dose¹ C_(max) AUC₁₂₀₀ Example (mg) n² (μg/mL) (μg-hr/mL)Example 18 50 1 1.41 9.63 Control 8 50 2 0.28 3.12 ¹The average weightof the dogs used in this study was around 9 kg ²Number of dogs studied

These data demonstrate that the physical mixture of HPMCAS and Drug 6,when colonically dosed to a beagle dog, gave a higher systemic Drug 6exposure than that obtained by dosing the Drug 6 alone. The C_(max) andAUC₁₂₀₀ for the HPMCAS form was 5.0-fold and 3.1-fold that of thecontrol, respectively. These data demonstrate the utility of theinvention in delivery of compounds to the colon.

Example 19

Example 19 demonstrates a composition similar to that used in Example 18that was also tested in vitro as follows. Example 19 was prepared byfirst adding 20 mL deionized water to a small glass beaker, andadjusting the pH to between pH 1 and 2, with 10 M HCl. Next, 100 mg ofDrug 6 was dissolved in this solution by stirring for 5 minutes. Duringthis time the pH remained in the range of 1-2, resulting in a final Drug6 concentration of 5 mg/mL.

This mixture of Drug 6 was then equally divided into two small glassbeakers, each containing a magnetic stir bar. A 10 mg sample ofHPMCAS-LF was added to one beaker (Example 19) and noconcentration-enhancing polymer was added to the second beaker (Control9).

Thus, the drug/polymer ratio in this test was 1:4 (wt:wt). The pH ofboth was then adjusted to pH 6.8 using 0.1 M and 0.01 M NaOH. Thebeakers were covered and the mixtures stirred.

Samples (≈1 mL) were taken at 60, 120, 180, 240 and 1440 minutes using aglass Pasteur pipette. Each sample was transferred into a 1.0 mL plasticsyringe with a Gelman Acrodisc 1.2 μm syringe filter attached. Thesample was then expelled through the filter into a glass HPLC injectionvial, capped, immediately assayed by HPLC, and compound concentrationcalculated. Samples were analyzed using a Zorbax C8 Reverse Phase, 5 μm,4.6×150 mm column with detection at 264 nm.

The results of these tests are given in Tables 9.1 and 9.2. They showthat the C of Example 19 was 2.5-fold that of Control 9. In addition,the AUC₁₈₀ for Example 19 was 3.7-fold that of Control 9. These dataagree well with the in vivo tests described in Example 18.

TABLE 9.1 [Drug 6] (μg/mL) Time Example 19 Control 9 (min) (1:4 Drug6:HPMCAS-LF) (Drug 6 only) 60 46 21 120 52 7 180 47 9 240 51 6 1440 36 4

TABLE 9.2 Theoretical C_(max) AUC₁₈₀ C_(max) Sample (μg/mL) (min*μg/mL)(μg/mL) Example 19 52 7290 250 (1:4 Drug 6:HPMCAS-LF) Control 9 21 1950250 (Drug 6 only)

Example 20

The formation of polymer/drug aggregates in solution was demonstratedusing dynamic light-scattering analysis. Varying amounts of amorphousDrug 1 and HPMCAS-MF were added to PBS, and light-scattering wasmeasured using a PSS-NICOMP 380 Submicron Particle Sizer. For theseexperiments, 0.1, 1.0, 10.0, 25.0, or 50.0 mg of solid amorphous Drug 1was added to a mortar with 200 mg of HPMCAS-MF, and mixed using aspatula. Each drug/polymer mixture was then added to 50 mL PBSequilibrated to 37° C. for two hours. Table 10 shows the final polymerand drug concentrations present in the solution. After 2 hours, 1 mL ofsolution was removed and centrifuged at 13,000 rpm for five minutes.Dynamic light-scattering (based on diffusion of particles) of thesupernatant of each of the centrifuged solutions was measured, and thesize of any drug and polymer particles in the solution was calculated.Concentrations of drug and polymer in solution, and the correspondingaverage particle size for the bulk of particles in solution are shown inTable 10. It should be noted for solutions No. 5 and No. 6, the valuereported is an average with approximately 85% of the particle volumebeing within about 30% of this average size.

TABLE 10 Drug 1 HPMCAS-MF Particle Solution Concentration ConcentrationSize No. (mg/mL) (mg/mL) (nm) 1 0 2.0 12 2 0.002 2.0 18 3 0.02 2.0 16 40.2 2.0 14 5 0.5 2.0 84 6 1.0 2.0 83

When no drug is present (solution No. 1), small particles about 10 to 20nm in size are present due to aggregation of the polymer (HPMCAS-MF),likely as a result of its amphiphilicity. At low concentrations ofamorphous Drug 1 (0.002 to 0.2 mg/mL), light-scattering shows only smallparticles in solution (about 10 to 20 nm in size), as are present forpolymer alone. For higher concentrations of amorphous Drug 1 (≧0.5mg/mL), which are above the solubility of amorphous Drug 1(approximately 0.2 to 0.4 mg/mL) particles are present with an averagesize of about 80 to 85 nm. This demonstrates the formation ofpolymer/drug aggregates in solution, and shows that the amount of drugrequired for aggregate formation is approximately equal to or greaterthan the amorphous drug solubility.

The concentration-enhancement provided by these polymer/drug aggregateswas demonstrated for Drug 1 concentrations higher than those shown inTable 10 (much greater than the amorphous drug solubility). For thedissolution test described in Example 9, 10.0 mg/mL amorphous Drug 1 wasadded to PBS at 37° C., with 20 mg/mL HPMCAS-MF. The control for Example9 was amorphous drug alone. Drug 1 concentrations measured at 1.5 hoursshowed 224 μg/mL for amorphous drug alone, and 8,099 μg/mL for Example9. The ratio of drug to polymer for Example 9 corresponds to the ratioused in solution No. 6 above (Table 10). The formation of drug/polymeraggregates in solution allowed Drug 1 to remain in solution at aconcentration far in excess of its amorphous solubility.

To determine the drug/polymer aggregate compositions, solutions No. 4,No. 5, and No. 6 above (Table 10) were made again and analyzed usingHPLC and NMR. Drug and polymer were added to PBS at 37° C. Two hoursafter the addition of drug and polymer samples were centrifuged (13,000rpm for 5 minutes). The concentrations of free drug and free polymer inthe supernatant were determined by NMR. HPLC was used to determine thetotal amount of dissolved drug in the supernatant followingcentrifugation which consists of “free” (solvated) drug and drug inpolymer/drug aggregates. The centrifuged precipitate was dissolved inDMSO and analyzed by NMR to obtain the concentrations of drug andpolymer. The amount of drug contained in the drug/polymer aggregates wasfound by subtracting the concentration of free drug in the supernatantfrom the total dissolved drug. The amount of polymer contained in thedrug/polymer aggregates was found by subtracting the free polymer andthe polymer in the precipitate from the total polymer dosed. The resultsare shown in Table 11 below.

TABLE 11 Free Free Drug 1 Polymer Total HPMCAS- Conc. Conc. TotalPolymer Drug 1 Polymer Drug 1 MF In In Dissolved Drug 1 in in inSolution Conc. Conc. Solution Solution Drug 1 in Precipitate PrecipitateAggregates Aggregates (No.) (μg/mL) (μg/mL) (μg/mL) (μg/mL) (μg/mL)(μg/mL) (μg/mL) (μg/mL) (μg/mL) 4 200 2000 166 1770 198 0 0 32 230 5 5002000 265 1367 462 47 88 197 545 6 1000 2000 301 1004 542 377 535 241 461

The data in Table 11 show that for drug concentrations exceeding thesolubility limit (solutions No. 5 and No. 6), a large percentage of thetotal soluble drug is contained in drug-polymer aggregates. In addition,the free drug concentration for solution No. 6 is about 3.8-fold thesolubility of the crystalline Drug 1 (80 μg/mL) and about 1.5-fold thesolubility of amorphous Drug 1 (200 μg/mL).

The terms and expressions which have been employed in the foregoingspecification are used therein as terms of description and not oflimitation, and there is no intention, in the use of such terms andexpressions, of excluding equivalents of the features shown anddescribed or portions thereof, it being recognized that the scope of theinvention is defined and limited only by the claims which follow.

1. A composition comprising: (a) a drug in a pharmaceutically acceptablesolubility-improved form that is a crystalline highly soluble salt formother than the crystalline hydrochloride salt; and (b) aconcentration-enhancing polymer selected from the group consisting ofhydroxypropyl methyl cellulose acetate, hydroxypropyl methyl cellulose,hydroxypropyl cellulose, methyl cellulose, hydroxyethyl methylcellulose, hydroxyethyl cellulose acetate, hydroxyethyl ethyl cellulose,and mixtures thereof wherein said drug alone has an aqueous solubilityof up to 2 mg/mL at pH 1 to 8, said composition is not a dispersion andsaid drug and said polymer are present as particles in a dry physicalmixture.
 2. A composition comprising: (a) a drug in a pharmaceuticallyacceptable solubility-improved form that is a crystalline highly solublesalt form other than the crystalline hydrochloride salt; and (b) aconcentration-enhancing polymer selected from the group consisting ofcarboxymethyl ethyl cellulose wherein said drug alone has an aqueoussolubility of up to 2 mg/mL at pH 1 to 8, said composition is not adispersion and said drug and said polymer are present as particles in adry physical mixture.
 3. A composition comprising: (a) a drug in apharmaceutically acceptable solubility-improved form that is acrystalline highly soluble salt form other than the crystallinehydrochloride salt; and (b) a concentration-enhancing polymer selectedfrom the group consisting of acrylate and methacrylate copolymerswherein said drug alone has an aqueous solubility of up to 2 mg/mL at pH1 to 8, said composition is not a dispersion and said drug and saidpolymer are present as particles in a dry physical mixture.
 4. Thecomposition of any of claims 1-3 wherein said crystalline highly solublesalt form is selected from the group consisting of bromide, acetate,iodide, mesylate, phosphate, maleate, citrate, sulfate, tartrate, andlactate salts.
 5. The composition of any of claims 1-3 wherein saidcrystalline highly soluble salt form is selected from the groupconsisting of sodium, calcium, potassium, zinc, magnesium, lithium,aluminum, meglumine, diethanolamine, benzathine, choline, and procainesalts.
 6. The composition of any of claims 1-3 wherein said drug alonehas an aqueous solubility of less than 0.01 mg/mL at pH 1 to
 8. 7. Thecomposition of any of claims 1-3 wherein said drug is selected fromantihypertensives, antianxiety agents, anticlotting agents,anticonvulsants, blood glucose-lowering agents, decongestants,antihistamines, antitussives, antineoplastics, beta blockers,anti-inflammatories, antipsychotic agents, cognitive enhancers,cholesterol-reducing agents, antiobesity agents, autoimmune disorderagents, anti-impotence agents, antibacterial and antifungal agents,hypnotic agents, anti-parkinsonism agents, anti-Alzheimer's diseaseagents, antibiotics, anti-depressants, and antiviral agents.